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X-linked reticulate pigmentary disorder (XLPDR, Mendelian Inheritance in Man #301220) is a rare syndrome characterized by recurrent infections and sterile multiorgan inflammation. The syndrome is caused by an intronic mutation in POLA1, the gene encoding the catalytic subunit of DNA polymerase-α (Pol-α), which is responsible for Okazaki fragment synthesis during DNA replication. Reduced POLA1 expression in this condition triggers spontaneous type I interferon expression, which can be linked to the autoinflammatory manifestations of the disease. However, the history of recurrent infections in this syndrome is as yet unexplained. Here we report that patients with XLPDR have reduced NK cell cytotoxic activity and decreased numbers of NK cells, particularly differentiated, stage V, cells (CD3-CD56dim). This phenotype is reminiscent of hypomorphic mutations in MCM4, which encodes a component of the minichromosome maintenance (MCM) helicase complex that is functionally linked to Pol-α during the DNA replication process. We find that POLA1 deficiency leads to MCM4 depletion and that both can impair NK cell natural cytotoxicity and show that this is due to a defect in lytic granule polarization. Altogether, our study provides mechanistic connections between Pol-α and the MCM complex and demonstrates their relevance in NK cell function.

We describe a unique male with a dicentric Y chromosome whose phenotype was compared to that of males with 47,XYY (XYY). The male Y-chromosome aneuploidy XYY is associated with physical, behavioral/cognitive phenotypes, and autism spectrum disorders. We hypothesize that increased risk for these phenotypes is caused by increased copy number/overexpression of Y-encoded genes. Specifically, an extra copy of the neuroligin gene NLGN4Y might elevate the risk of autism in boys with XYY. We present a unique male with the karyotype 46,X,idic(Y)(q11.22), which includes duplication of the Y short arm and proximal long arm and deletion of the distal long arm, evaluated his physical, behavioral/cognitive, and neuroimaging/magnetoencephalography (MEG) phenotypes, and measured blood RNA expression of Y genes. The proband had tall stature and cognitive function within the typical range, without autism features. His blood RNA showed twofold increase in expression of Yp genes versus XY controls, and absent expression of deleted Yq genes, including NLGN4Y. The M100 latencies were similar to findings in typically developing males. In summary, the proband had overexpression of a subset of Yp genes, absent NLGN4Y expression, without ASD findings or XYY-MEG latency findings. These results are consistent with a role for NLGN4Y overexpression in the etiology of behavioral phenotypes associated with XYY. Further investigation of NLGN4Y as an ASD risk gene in XYY is warranted. The genotype and phenotype(s) of this subject may also provide insight into how Y chromosome genes contribute to normal male development and the male predominance in ASD., (© 2019 Wiley Periodicals, Inc.)

A fundamental question in the biology of sex differences has eluded direct study in humans: How does sex-chromosome dosage (SCD) shape genome function? To address this, we developed a systematic map of SCD effects on gene function by analyzing genome-wide expression data in humans with diverse sex-chromosome aneuploidies (XO, XXX, XXY, XYY, and XXYY). For sex chromosomes, we demonstrate a pattern of obligate dosage sensitivity among evolutionarily preserved X-Y homologs and update prevailing theoretical models for SCD compensation by detecting X-linked genes that increase expression with decreasing X- and/or Y-chromosome dosage. We further show that SCD-sensitive sex-chromosome genes regulate specific coexpression networks of SCD-sensitive autosomal genes with critical cellular functions and a demonstrable potential to mediate previously documented SCD effects on disease. These gene coexpression results converge with analysis of transcription factor binding site enrichment and measures of gene expression in murine knockout models to spotlight the dosage-sensitive X-linked transcription factor ZFX as a key mediator of SCD effects on wider genome expression. Our findings characterize the effects of SCD broadly across the genome, with potential implications for human phenotypic variation., Competing Interests: The authors declare no conflict of interest.

Short stature homeobox gene (SHOX) is located in the pseudoautosomal region 1 of the sex chromosomes. It encodes a transcription factor implicated in the skeletal growth. Point mutations, deletions or duplications of SHOX or its transcriptional regulatory elements are associated with two skeletal dysplasias, Léri-Weill dyschondrosteosis (LWD) and Langer mesomelic dysplasia (LMD), as well as in a small proportion of idiopathic short stature (ISS) individuals. We have identified a total of 15 partial SHOX deletions and 13 partial SHOX duplications in LWD, LMD and ISS patients referred for routine SHOX diagnostics during a 10 year period (2004-2014). Subsequently, we characterized these alterations using MLPA (multiplex ligation-dependent probe amplification assay), fine-tiling array CGH (comparative genomic hybridation) and breakpoint PCR. Nearly half of the alterations have a distal or proximal breakpoint in intron 3. Evaluation of our data and that in the literature reveals that although partial deletions and duplications only account for a small fraction of SHOX alterations, intron 3 appears to be a breakpoint hotspot, with alterations arising by non-allelic homologous recombination, non-homologous end joining or other complex mechanisms.

Aberrant nucleic acids generated during viral replication are the main trigger for antiviral immunity, and mutations that disrupt nucleic acid metabolism can lead to autoinflammatory disorders. Here we investigated the etiology of X-linked reticulate pigmentary disorder (XLPDR), a primary immunodeficiency with autoinflammatory features. We discovered that XLPDR is caused by an intronic mutation that disrupts the expression of POLA1, which encodes the catalytic subunit of DNA polymerase-α. Unexpectedly, POLA1 deficiency resulted in increased production of type I interferons. This enzyme is necessary for the synthesis of RNA:DNA primers during DNA replication and, strikingly, we found that POLA1 is also required for the synthesis of cytosolic RNA:DNA, which directly modulates interferon activation. Together this work identifies POLA1 as a critical regulator of the type I interferon response.

Single-minded 1 (Sim1) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that is important for neuronal development in the hypothalamus. Loss-of-function mutation of Sim1 causes early-onset obesity. However, it is unknown whether and how Sim1 regulates bone remodeling. In this study, we found that adult-onset Sim1 deletion increases bone formation, leading to high bone mass. In contrast, Sim1-overexpressing transgenic mice exhibit decreased bone formation and low bone mass. Sim1 does not directly regulate osteoblastogenesis, because bone marrow mesenchymal stem cells from Sim1 mutant mice display a normal capacity for osteoblast differentiation. Instead, Sim1 inhibits bone formation via stimulating the sympathetic nervous system, because sympathetic tone is decreased by Sim1 deletion but increased by Sim1 overexpression. Treatment with the β-adrenergic agonist isoproterenol effectively reverses the high bone mass in Sim1-knockout mice. These findings reveal Sim1 as a critical yet previously unrecognized modulator of skeletal homeostasis that functions through a central relay.

The male sex chromosome disorder, 47,XYY syndrome (XYY), is associated with increased risk for social-emotional difficulties, attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We hypothesize that increased Y chromosome gene copy number in XYY leads to overexpression of Y-linked genes related to brain development and function, thereby increasing risk for these phenotypes. We measured expression in blood of two Y genes NLGN4Y and RPS4Y in 26 boys with XYY and 11 male controls and evaluated whether NLGN4Y expression correlates with anxiety, ADHD, depression and autistic behaviors (from questionnaires) in boys with XYY. The XYY cohort had increased risk of ASD behaviors on the social responsiveness scale (SRS) and increased attention deficits on the Conners' DSM-IV inattention and hyperactive scales. In contrast, there was no increase in reported symptoms of anxiety or depression by the XYY group. Peripheral expression of two Y genes in boys with XYY vs. typically developing controls was increased twofold in the XYY group. Results from the SRS total and autistic mannerisms scales, but not from the attention, anxiety or depression measures, correlated with peripheral expression of NLGN4Y in boys with XYY. Males with XYY have social phenotypes that include increased risk for autism-related behaviors and ADHD. Expression of NLGN4Y, a gene that may be involved in synaptic function, is increased in boys with XYY, and the level of expression correlates with overall social responsiveness and autism symptoms. Thus, further investigation of NLGN4Y as a plausible ASD risk gene in XYY is warranted., (© 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

Germline haploinsufficiency of human or mouse Sim1 is associated with hyperphagic obesity. Sim1 encodes a transcription factor required for proper formation of the paraventricular (PVN), supraoptic, and anterior periventricular hypothalamic nuclei. Sim1 expression persists in these neurons in adult mice, raising the question of whether it plays a physiologic role in regulation of energy balance. We previously showed that Sim1 heterozygous mice had normal numbers of PVN neurons that were hyporesponsive to melanocortin 4 receptor agonism and showed reduced oxytocin expression. Furthermore, conditional postnatal neuronal inactivation of Sim1 also caused hyperphagic obesity and decreased hypothalamic oxytocin expression. PVN projections to the hindbrain, where oxytocin is thought to act to modulate satiety, were anatomically intact in both Sim1 heterozygous and conditional knockout mice. These experiments provided evidence that Sim1 functions in energy balance apart from its role in hypothalamic development but did not rule out effects of Sim1 deficiency on postnatal hypothalamic maturation. To address this possibility, we used a tamoxifen-inducible, neural-specific Cre transgene to conditionally inactivate Sim1 in adult mice with mature hypothalamic circuitry. Induced Sim1 inactivation caused increased food and water intake and decreased expression of PVN neuropeptides, especially oxytocin and vasopressin, with no change in energy expenditure. Sim1 expression was not required for survival of PVN neurons. The results corroborate previous evidence that Sim1 acts physiologically as well as developmentally to regulate body weight. Inducible knockout mice provide a system for studying Sim1's physiologic function in energy balance and identifying its relevant transcriptional targets in the hypothalamus.

The NR5A1 gene encodes for steroidogenic factor 1, a nuclear receptor that regulates proper adrenal and gonadal development and function. Mutations identified by NR5A1 sequencing have been associated with disorders of sex development (DSD), ranging from sex reversal to severe hypospadias in 46,XY patients and premature ovarian failure (POF) in 46,XX patients. Previous reports have identified four families with a history of both 46,XY DSD and 46,XX POF carrying segregating NR5A1 sequence mutations. Recently, three 46,XY DSD sporadic cases with NR5A1 microdeletions have been reported. Here, we identify the first NR5A1 microdeletion transmitted in a pedigree with both 46,XY DSD and 46,XX POF. A 46,XY individual with DSD due to gonadal dysgenesis was born to a young mother who developed POF. Array CGH analysis revealed a maternally inherited 0.23 Mb microdeletion of chromosome 9q33.3, including the NR5A1 gene. Based on this finding, we screened patients with unexplained 46,XY DSD (n = 11), proximal hypospadias (n = 21) and 46,XX POF (n = 36) for possible NR5A1 copy-number variations (CNVs) via multiplex ligation-dependent probe amplification (MLPA), but did not identify any additional CNVs involving NR5A1. These data suggest that NR5A1 CNVs are an infrequent cause of these disorders but that array CGH and MLPA are useful genomic screening tools to uncover the genetic basis of such unexplained cases. This case is the first report of a familial NR5A1 CNV transmitting in a pedigree, causing both the male and female phenotypes associated with NR5A1 mutations, and the first report of a NR5A1 CNV associated with POF., (Copyright © 2013 Wiley Periodicals, Inc.)

Hypoplastic left heart syndrome (HLHS), one of the most severe types of congenital heart disease (CHD), results in significant morbidity and mortality despite surgical palliation. The etiology of HLHS is unknown, but evidence supports genetic contributors. The authors hypothesized that submicroscopic chromosomal abnormalities exist in individuals with HLHS and are more frequent in those with additional birth defects. This study sought to determine the incidence and genomic location of submicroscopic chromosomal abnormalities in HLHS and potentially to identify novel genetic loci that may contribute to the disease. For this study, 43 children with HLHS were recruited and screened together with a control population of 16 subjects using array comparative genomic hybridization, also called chromosomal microarray, for chromosomal copy number variations (CNVs). A statistically greater number of CNVs were found in the HLHS group than in the control group (p < 0.03). The CNVs were predominantly small autosomal deletions and duplications (≤ 60,000 bp). The frequency of unique CNVs, those not previously reported in public databases, did not differ statistically between the HLHS subjects and the control subjects. No difference in the frequency of CNVs was noted between the patients with HLHS and additional anomalies and those with isolated HLHS. The identified CNVs did not harbor potential candidate genes for HLHS, but one microdeletion was located on chromosome 14q23, a genetic locus linked to left-sided CHD. The study data demonstrate that CNVs, specifically those relatively small in size, are more common in subjects with HLHS, but the frequency of large potentially disease-causing CNVs (>480,000 bp) did not differ between the HLHS and control populations.

Objective: To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype., Methods: Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4-15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments., Results: Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners' Parent Rating Scale-Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors., Conclusions: A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.

We studied a man with distal hypospadias, partial anomalous pulmonary venous return, mild limb-length inequality and a balanced translocation involving chromosomes 9 and 13. To gain insight into the etiology of his birth defects, we mapped the translocation breakpoints by high-resolution comparative genomic hybridization (CGH), using chromosome 9- and 13-specific tiling arrays to analyze genetic material from a spontaneously aborted fetus with unbalanced segregation of the translocation. The chromosome 13 breakpoint was ∼400  kb away from the nearest gene, but the chromosome 9 breakpoint fell within an intron of Basonuclin 2 (BNC2), a gene that encodes an evolutionarily conserved nuclear zinc-finger protein. The BNC2/Bnc2 gene is abundantly expressed in developing mouse and human periurethral tissues. In all, 6 of 48 unrelated subjects with distal hypospadias had nine novel nonsynonymous substitutions in BNC2, five of which were computationally predicted to be deleterious. In comparison, two of 23 controls with normal penile urethra morphology, each had a novel nonsynonymous substitution in BNC2, one of which was predicted to be deleterious. Bnc2(-/-) mice of both sexes displayed a high frequency of distal urethral defects; heterozygotes showed similar defects with reduced penetrance. The association of BNC2 disruption with distal urethral defects and the gene's expression pattern indicate that it functions in urethral development.

Context: Léri-Weill dyschondrosteosis (LWD) is a skeletal dysplasia characterized by disproportionate short stature and the Madelung deformity of the forearm. SHOX mutations and pseudoautosomal region 1 deletions encompassing SHOX or its enhancers have been identified in approximately 60% of LWD and approximately 15% of idiopathic short stature (ISS) individuals. Recently SHOX duplications have been described in LWD/ISS but also in individuals with other clinical manifestations, thus questioning their pathogenicity., Objective: The objective of the study was to investigate the pathogenicity of SHOX duplications in LWD and ISS., Design and Methods: Multiplex ligation-dependent probe amplification is routinely used in our unit to analyze for SHOX/pseudoautosomal region 1 copy number changes in LWD/ISS referrals. Quantitative PCR, microsatellite marker, and fluorescence in situ hybridization analysis were undertaken to confirm all identified duplications., Results: During the routine analysis of 122 LWD and 613 ISS referrals, a total of four complete and 10 partial SHOX duplications or multiple copy number (n > 3) as well as one duplication of the SHOX 5' flanking region were identified in nine LWD and six ISS cases. Partial SHOX duplications appeared to have a more deleterious effect on skeletal dysplasia and height gain than complete SHOX duplications. Importantly, no increase in SHOX copy number was identified in 340 individuals with normal stature or 104 overgrowth referrals., Conclusion: MLPA analysis of SHOX/PAR1 led to the identification of partial and complete SHOX duplications or multiple copies associated with LWD or ISS, suggesting that they may represent an additional class of mutations implicated in the molecular etiology of these clinical entities.

Diet and sedentary lifestyle, interacting with "thrifty" genes, are widely accepted as the principal cause of the current global obesity epidemic. However, a number of alternative etiologies for obesity have been proposed, including "drifty" genes, viruses, bacteria, environmental toxins, social network effects, maternal imprinting, sleep deprivation, and others. These Grand Rounds reviews the background of some of these unconventional ideas and evidence for or against their roles in the obesity epidemic.

We describe three patients with a comparable deletion encompassing SLC25A43, SLC25A5, CXorf56, UBE2A, NKRF, and two non-coding RNA genes, U1 and LOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures, and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. These clinical features overlap with those described in two patients from a family with a similar deletion at Xq24 that also includes UBE2A, and in several patients of Brazilian and Polish families with point mutations in UBE2A. Notably, all five patients with an Xq24 deletion have ventricular septal defects that are not present in patients with a point mutation, which might be attributed to the deletion of SLC25A5. Taken together, the UBE2A deficiency syndrome in male patients with a mutation in or a deletion of UBE2A is characterized by ID, absent speech, seizures, urogenital anomalies, frequently including a small penis, and skin abnormalities, which include generalized hirsutism, low posterior hairline, myxedematous appearance, widely spaced nipples, and hair whorls. Facial dysmorphisms include a wide face, a depressed nasal bridge, a large mouth with downturned corners, thin vermilion, and a short, broad neck., (© 2010 Wiley-Liss, Inc.)

PKC-theta (PKC-θ), a member of the novel protein kinase C family (nPKC), regulates a wide variety of functions in the periphery. However, its presence and role in the CNS has remained largely unknown. Recently, we demonstrated the presence of PKC-θ in the arcuate hypothalamic nucleus (ARC) and knockdown of PKC-θ from the ARC protected mice from developing diet-induced obesity. Another isoform of the nPKC group, PKC-delta (PKC-δ), is expressed in several non-hypothalamic brain sites including the thalamus and hippocampus. Although PKC-δ has been implicated in regulating hypothalamic glucose homeostasis, its distribution in the hypothalamus has not previously been described. In the current study, we used immunohistochemistry to examine the distribution of PKC-θ and -δ immunoreactivity in rat and mouse hypothalamus. We found PKC-θ immunoreactive neurons in several hypothalamic nuclei including the ARC, lateral hypothalamic area, perifornical area and tuberomammillary nucleus. PKC-δ immunoreactive neurons were found in the paraventricular and supraoptic nuclei. Double-label immunohistochemisty in mice expressing green fluorescent protein either with the long form of leptin receptor (LepR-b) or in orexin (ORX) neurons indicated that PKC-θ is highly colocalized in lateral hypothalamic ORX neurons but not in lateral hypothalamic LepR-b neurons. Double-label immunohistochemistry in oxytocin-enhanced yellow fluorescent protein mice or arginine vasopressin-enhanced green fluorescent protein (AVP-EGFP) transgenic rats revealed a high degree of colocalization of PKC-δ within paraventricular and supraoptic oxytocin neurons but not the vasopressinergic neurons. We conclude that PKC-θ and -δ are expressed in different hypothalamic neuronal populations., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT(2C)Rs) significantly attenuated D-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT(2C)Rs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of D-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of D-Fen. Thus, our results identify a neurochemically defined neural circuit through which D-Fen influences appetite and thereby indicate that this 5-HT(2C)R/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.

Single-minded 1 (SIM1) mutations are one of the few known causes of nonsyndromic monogenic obesity in both humans and mice. Although the role of Sim1 in the formation of the hypothalamus has been described, its postdevelopmental, physiological functions have not been well established. Here we demonstrate that postnatal CNS deficiency of Sim1 is sufficient to cause hyperphagic obesity. We conditionally deleted Sim1 after birth using CaMKII-Cre (alpha-calcium/calmodulin-dependent protein kinase II-Cre) lines to recombine a floxed Sim1 allele. Conditional Sim1 heterozygotes phenocopied germ line Sim1 heterozygotes, displaying hyperphagic obesity and increased length. We also generated viable conditional Sim1 homozygotes, demonstrating that adult Sim1 expression is not essential for mouse or neuron survival and revealing a dosage-dependent effect of Sim1 on obesity. Using stereological cell counting, we showed that the phenotype of both germ line heterozygotes and conditional Sim1 homozygotes was not attributable to global hypocellularity of the paraventricular nucleus (PVN) of the hypothalamus. We also used retrograde tract tracing to demonstrate that the PVN of germ line heterozygous mice projects normally to the dorsal vagal complex and the median eminence. Finally, we showed that conditional Sim1 homozygotes and germ line Sim1 heterozygotes exhibit a remarkable decrease in hypothalamic oxytocin (Oxt) and PVN melanocortin 4 receptor (Mc4r) mRNA. These results demonstrate that the role of Sim1 in feeding regulation is not limited to formation of the PVN or its projections and that the hyperphagic obesity in Sim1-deficient mice may be attributable to changes in the leptin-melanocortin-oxytocin pathway.

Background: Homozygous mutation of the short stature homeobox-containing gene, SHOX, results in Langer mesomelic dysplasia (LMD). Our case presented with severe short stature and skeletal deformities with Turner syndrome (TS) and a SHOX gene abnormality due to a downstream allele deletion in her normal X chromosome. Medical literature review did not reveal similar cases that were treated with GH therapy., Method: We present an 11-yr-old with combined TS and LMD with severe short stature and skeletal deformities. She was studied for the effect of GH therapy on stature and skeletal deformities. Karyotype testing showed 45,X/46,X,idic(X). Genetic analysis of SHOX gene testing did not detect any exonic mutations. Interestingly, both alleles of the flanking marker DXYS233, a marker downstream of the 3' end of SHOX coding sequence, were absent with resultant LMD. GH therapy in the mean dose of 0.321 mg/kg/wk was administered for 4 yr (0.287, 0.355, 0.317, and 0.327 mg/kg/week in the first, second, third, and fourth years, respectively). Clinical data were reviewed., Result: The growth rates of 3.46, 3.87, 2.3, and 0.7 cm/yr were observed in the first, second, third, and fourth years of the GH therapy, respectively. There was no clinical deterioration of the skeletal deformities., Conclusion: There was a failure to achieve growth improvements with GH therapy for 4 years, but there was no worsening of the skeletal deformities. We conclude that GH therapy may not be beneficial in severe short stature due to combined TS and LMD resulting from homozygous SHOX deficiency.

Background: Statistical power calculations are a critical part of any study design for gene mapping. Most calculations assume that the locus of interest is biallelic. However, there are common situations in human genetics such as X-linked loci in males where the locus is haploid. The purpose of this work is to mathematically derive the biometric model for haploid loci, and to compute power for QTL mapping when the loci are haploid., Results: We have derived the biometric model for power calculations for haploid loci and have developed software to perform these calculations. We have verified our calculations with independent mathematical methods., Conclusion: Our results fill a need in power calculations for QTL mapping studies. Furthermore, failure to appropriately model haploid loci may cause underestimation of power.

Background: Characterization of disease-associated balanced translocations has led to the discovery of genes responsible for many disorders, including syndromes that include various forms of diabetes mellitus. We studied a man with unexplained maturity onset diabetes of the young (MODY)-like diabetes and an apparently balanced translocation [46,XY,t(7;10)(q22;p12)] and sought to identify a novel diabetes locus by characterizing the translocation breakpoints., Results: Mutations in coding exons and splice sites of known MODY genes were first ruled out by PCR amplification and DNA sequencing. Fluorescent in situ hybridization (FISH) studies demonstrated that the translocation did not disrupt two known diabetes-related genes on 10p12. The translocation breakpoints were further mapped to high resolution using FISH and somatic cell hybrids and the junctions PCR-amplified and sequenced. The translocation did not disrupt any annotated transcription unit. However, the chromosome 10 breakpoint was 220 kilobases 5' to the Membrane Protein, Palmitoylated 7 (MPP7) gene, which encodes a protein required for proper cell polarity. This biological function is shared by HNF4A, a known MODY gene. Databases show MPP7 is highly expressed in mouse pancreas and is expressed in human islets. The translocation did not appear to alter lymphoblastoid expression of MPP7 or other genes near the breakpoints., Conclusion: The balanced translocation and MODY-like diabetes in the proband could be coincidental. Alternatively, the translocation may cause islet cell dysfunction by altering MPP7 expression in a subtle or tissue-specific fashion. The potential roles of MPP7 mutations in diabetes and perturbed islet cell polarity in insulin secretion warrant further study.

Objective: The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes., Methods: Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual-spatial abilities, visual-motor skills, and motor function., Results: Study cohort: 21 boys with 47,XYY and 93 boys with 47,XXY (KS), age 4-17 years, and 36 age-matched control boys. Both the XYY and KS groups performed less well, on average, than the controls on tests of general cognitive ability, achievement, language, verbal memory, some aspects of attention, and executive function, and motor function. The boys with XYY on average had more severe and pervasive language impairment, at both simple and complex levels, and the boys with KS on average had greater motor impairment in gross motor function and coordination, especially in running speed and agility., Conclusions: The results from these large XYY and KS cohorts have important neurocognitive and educational implications. From the neurocognitive standpoint, the presenting findings afford an opportunity to gain insights into brain development in boys with XYY and those with KS. From the educational standpoint, it is critical that boys with XYY or KS receive appropriate educational interventions that target their specific learning challenges. These findings also provide important information for counseling clinicians and families about these disorders.

Congenital heart disease (CHD) is the most common type of birth defect, and the etiology of most cases is unknown. CHD often occurs in association with other birth malformations, and only in a minority are disease-causing chromosomal abnormalities identified. We hypothesized that children with CHD and additional birth malformations have cryptic chromosomal abnormalities that might be uncovered using recently developed DNA microarray-based methodologies. We recruited 20 children with diverse forms of CHD and additional birth defects who had no chromosomal abnormality identified by conventional cytogenetic testing. Using whole-genome array comparative genomic hybridization, we screened this population, along with a matched control population with isolated heart defects, for chromosomal copy number variations. We discovered disease-causing cryptic chromosomal abnormalities in five children with CHD and additional birth defects versus none with isolated CHD. The chromosomal abnormalities included three unbalanced translocations, one interstitial duplication, and one interstitial deletion. The genetic abnormalities were predominantly identified in children with CHD and a neurologic abnormality. Our results suggest that a significant percentage of children with CHD and neurologic abnormalities harbor subtle chromosomal abnormalities. We propose that children who meet these two criteria should receive more extensive genetic testing to detect potential cryptic chromosomal abnormalities.

Single-minded 1 (Sim1) encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus (PVN). Sim1 haploinsufficiency is associated with hyperphagic obesity and increased linear growth in humans and mice, similar to the phenotype of melanocortin 4 receptor (Mc4r) mutations. PVN neurons in Sim1(+/-) mice are hyporesponsive to the melanocortin agonist melanotan II. PVN neuropeptides oxytocin (Oxt), TRH and CRH inhibit feeding when administered centrally. Consequently, we hypothesized that altered PVN neuropeptide expression mediates the hyperphagia of Sim1(+/-) mice. To test this hypothesis, we measured hypothalamic expression of PVN neuropeptides in Sim1(+/-) and wild-type mice. Oxt mRNA and peptide were decreased by 80% in Sim1(+/-) mice, whereas TRH, CRH, arginine vasopressin (Avp), and somatostatin mRNAs were decreased by 20-40%. Sim1(+/-) mice also showed abnormal regulation of Oxt but not CRH mRNA in response to feeding state. A selective Mc4r agonist activated PVN Oxt neurons in wild-type mice, supporting involvement of these neurons in melanocortin feeding circuits. To test whether Oxt itself regulates feeding, we measured the effects of central administration of an Oxt receptor antagonist or repeated doses of Oxt on food intake of Sim1(+/-) and wild-type mice. Sim1(+/-) mice were hypersensitive to the orexigenic effect of the Oxt receptor antagonist. Oxt decreased the food intake and weight gain of Sim1(+/-) mice at a dose that did not affect wild-type mice. Our results support the importance of Oxt neurons in feeding regulation and suggest that reduced Oxt neuropeptide is one mechanism mediating the hyperphagic obesity of Sim1(+/-) mice.

The neurocognitive phenotype of Turner syndrome (TS) includes deficits in social cognitive skills such as recognition of the facial affect expressing fear. A TS social cognition locus was previously mapped to a 5 megabase interval of Xp11.3-p11.4 by Good et al. 2003. A recent study by these same workers found evidence for association of a SNP in the EFHC2 gene, rs7055196, within this interval with fear recognition in 45,X TS. As EFHC2 was not a biological candidate gene for this phenotype a priori, we sought to replicate their finding in an independent cohort of 45,X TS subjects, using the same instrument to measure facial affect fear recognition. In contrast to the previous results, we find no evidence of an association between rs7055196 genotype and fear recognition. Other variations in EFHC2 and other candidate genes should be tested for association with social cognition in 45,X TS., ((c) 2007 Wiley-Liss, Inc.)

X-linked reticulate pigmentary disorder with systemic manifestations in males (PDR) is very rare. Affected males are characterized by cutaneous and visceral symptoms suggestive of abnormally regulated inflammation. A genetic linkage study of a large Canadian kindred previously mapped the PDR gene to a greater than 40 Mb interval of Xp22-p21. The aim of this study was to identify the causative gene for PDR. The Canadian pedigree was expanded and additional PDR families recruited. Genetic linkage was performed using newer microsatellite markers. Positional and functional candidate genes were screened by PCR and sequencing of coding exons in affected males. The location of the PDR gene was narrowed to a approximately 4.9 Mb interval of Xp22.11-p21.3 between markers DXS1052 and DXS1061. All annotated coding exons within this interval were sequenced in one affected male from each of the three multiplex families as well as one singleton, but no causative mutation was identified. Sequencing of other X-linked genes outside of the linked interval also failed to identify the cause of PDR but revealed a novel nonsynonymous cSNP in the GRPR gene in the Maltese population. PDR is most likely due to a mutation within the linked interval not affecting currently annotated coding exons.

Objective: To describe the Klinefelter Syndrome (KS) phenotype during childhood in a large cohort., Study Design: Clinical assessment, measurement of hormonal indices of testicular function, and parent of origin of extra X chromosome were assessed in a cross-sectional study of 55 boys with KS, aged 2.0 to 14.6 years, at an outpatient center., Results: Mean height and body mass index SD scores (SDS +/- SD) were 0.9 +/- 1.3 and 0.4 +/- 1.4, respectively. Mean penile length and testicular volume SDS were -0.5 +/- 0.9 and -0.9 +/- 1.4. Testosterone levels were in the lowest quartile of normal in 66% of the cohort. Other features included clinodactyly (74%), hypertelorism (69%), elbow dysplasia (36%), high-arched palate (37%), hypotonia (76%), and requirement for speech therapy (69%). Features were similar in boys in whom the diagnosis was made prenatally versus boys in whom the diagnosis was made postnatally. There was no evidence for a phenotypic effect of parent of origin of the extra X chromosome., Conclusions: Boys with KS commonly have reduced penile length and small testes in childhood. The phenotype in boys with KS does not differ according to ascertainment or origin of the extra X chromosome. Boys with KS may be identified before puberty by tall stature, relatively decreased penile length, clinodactyly, hypotonia, and requirement for speech therapy.

The goal of this study was to expand the description of the cognitive development phenotype in boys with Klinefelter syndrome (47,XXY). We tested neuropsychological measures of memory, attention, visual-spatial abilities, visual-motor skills, and language. We examined the influence of age, handedness, genetic aspects (parental origin of the extra X chromosome, CAG(n) repeat length, and pattern of X inactivation), and previous testosterone treatment on cognition. We studied 50 boys with KS (4.1-17.8 years). There was a significant increase in left-handedness (P = 0.002). Specific language, academic, attentional, and motor abilities tended to be impaired. In the language domain, there was relative sparing of vocabulary and meaningful language understanding abilities but impairment of higher level linguistic competence. KS boys demonstrated an array of motor difficulties, especially in strength and running speed. Deficits in the ability to sustain attention without impulsivity were present in the younger boys. Neither genetic factors examined nor previous testosterone treatment accounted for variation in the cognitive phenotype in KS. The cognitive results from this large KS cohort may be related to atypical brain lateralization and have important diagnostic and psychoeducational implications. The difficulty in complex language processing, impaired attention and motor function in boys with KS may be missed. It is critical that boys with KS are provided with appropriate educational support that targets their learning challenges in school in addition to modifications that address their particular learning style. These findings would also be an important component of counseling clinicians and families about this disorder., ((c) 2008 Wiley-Liss, Inc.)

Background: The forkhead transcription factor Foxo3 is a master regulator and potent suppressor of primordial follicle activation. Loss of Foxo3 function in the mouse leads to premature ovarian failure (POF) due to global follicle activation., Methods and Results: Here, we show that the mouse Foxo3 locus is haploinsufficient, and that Foxo3-/+ females undergo early reproductive senescence consistent with an increased rate of primordial follicle utilization. Then, to determine if heterozygous or homozygous polymorphisms or mutations of the human orthologue FOXO3 contribute to POF or idiopathic primary amenorrhea (PA), we sequenced the exons and flanking splice sequences of the gene in a large number of women with idiopathic POF (n = 273) or PA (n = 29). A total of eight single-nucleotide polymorphisms (SNPs) were identified, revealing a substantial amount of genetic variation at this locus. Allelic frequencies in control samples excluded several of these variants as causal. For the remaining variants, site-directed mutagenesis was performed to assess their functional impact. However, these rare sequence variants were not associated with significant decreases in FOXO3 activity., Conclusions: Taken together, our findings suggest that, despite the potential for FOXO3 haploinsufficiency to cause ovarian failure, FOXO3 mutations or common SNPs are not a common cause of either POF or PA.

Phenotypically healthy carriers of the balanced 11;22 translocation, the most frequent non-Robertsonian constitutional translocation known in human beings, are at risk of having a progeny with supernumerary derivative (22)t(11;22) syndrome [der(22) syndrome]. We present the cases of 2 male patients with supernumerary der(22) syndrome [47,XY,+der(22)t(11;22)(q23;q11.2)mat], yielding partial trisomy for 22pter-q11 and 11q23-qter. These cases expand the phenotype of the der(22) syndrome, with the first case highlighting the phenotypic overlap of VACTERL and the second adding Hirschsprung's disease and intestinal malrotation to the list of associated anorectal anomalies. Because der(22) syndrome and cat eye syndrome (partial tetrasomy of 22q11) share a similar region of extra dosage on 22q11 and both typically manifest an anorectal phenotype, a dosage-sensitive gene for anorectal anomalies may be present in this locus.

Background: Turner syndrome (TS) is associated with a neurocognitive phenotype that includes selective nonverbal deficits, e.g., impaired visual-spatial abilities. We previously reported evidence that this phenotype results from haploinsufficiency of one or more genes on distal Xp. This inference was based on genotype/phenotype comparisons of individual girls and women with partial Xp deletions, with the neurocognitive phenotype considered a dichotomous trait. We sought to confirm our findings in a large cohort (n = 47) of adult women with partial deletions of Xp or Xq, enriched for subjects with distal Xp deletions., Methods: Subjects were recruited from North American genetics and endocrinology clinics. Phenotype assessment included measures of stature, ovarian function, and detailed neurocognitive testing. The neurocognitive phenotype was measured as a quantitative trait, the Turner Syndrome Cognitive Summary (TSCS) score, derived from discriminant function analysis. Genetic analysis included karyotyping, X inactivation studies, fluorescent in situ hybridization, microsatellite marker genotyping, and array comparative genomic hybridization., Results: We report statistical evidence that deletion of Xp22.3, an interval containing 31 annotated genes, is sufficient to cause the neurocognitive phenotype described by the TSCS score. Two other cardinal TS features, ovarian failure and short stature, as well as X chromosome inactivation pattern and subject's age, were unrelated to the TSCS score., Conclusion: Detailed mapping suggests that haploinsufficiency of one or more genes in Xp22.3, the distal 8.3 megabases (Mb) of the X chromosome, is responsible for a TS neurocognitive phenotype. This interval includes the 2.6 Mb Xp-Yp pseudoautosomal region (PAR1). Haploinsufficiency of the short stature gene SHOX in PAR1 probably does not cause this TS neurocognitive phenotype. Two genes proximal to PAR1 within the 8.3 Mb critical region, STS and NLGN4X, are attractive candidates for this neurocognitive phenotype.

We present the clinical and molecular characteristics of a multi-generation family in which the proband presented with clinical features of Langer mesomelic dysplasia (LMD) whilst different family members had a diagnosis of Léri-Weill dyschondrosteosis (LWD) and/or pseudoachondroplasia (PSACH). In the LMD proband two different deletions were identified in the pseudoautosomal 1 region (PAR1) of the X and Y chromosomes: a SHOX-encompassing deletion inherited from his father and a downstream PAR1 deletion, which did not include SHOX, inherited from his mother. The individuals with PSACH features presented the previously described G719D mutation in the C-terminal globular domain of the cartilage oligomeric matrix protein gene (COMP). The LMD proband described here represents the first LMD case due to compound heterozygosity for deletions of the two different PAR1 regions, SHOX-encompassing and downstream from SHOX, that have been shown to be implicated in the pathogenesis of LWD and LMD.

The tumor suppressor p53 is a key transcriptional factor regulating the induction of cellular senescence by oncogenic signals. The activity of p53 is regulated by recruitment into promyelocytic leukemia (PML)-nuclear bodies (NBs) as well as by stabilization through posttranslational modifications such as phosphorylation and acetylation. Here we found that MORC3 (microrchidia3)-ATPase activated p53 and induced cellular senescence in normal human and mouse fibroblasts but not p53-/- fibroblasts. Conversely, genotoxic stress-induced phosphorylation and stabilization of p53 but barely increased its transcriptional activity in Morc3-/- fibroblasts. MORC3 localized on PML-NBs in presence of PML and mediated recruitment of p53 and CREB-binding protein (CBP) into PML-NBs. In contrast, expression of ATPase activity-deficient mutant MORC3-E35A or siRNA repression of MORC3 impaired the localization of p53 and Sp100 but not CBP on PML-NBs. These results suggest that MORC3 regulates p53 activity and localization into PML-NBs. We identified a new molecular mechanism that regulates the activity of nuclear proteins by localization to a nuclear subdomain.

Certain behavioral and metabolic aspects of Turner syndrome (TS) are attributed to X-chromosome genomic imprinting. To investigate the possible contribution of imprinting to the physical features of the TS phenotype in live-born individuals, we genotyped the single normal X-chromosome in subjects with TS who all underwent a comprehensive evaluation as part of the NIH genotype-phenotype protocol. All had physical examinations, auxological measurements and imaging of the renal and cardiovascular systems. Absolute height and height as a percent of predicted height was the same in X(M) (n = 56) and X(P) (n = 23) subjects that had reached final height and were not growth hormone treated. Interestingly, adult height was significantly correlated with maternal but not paternal heights in both X(M) and X(P) groups. Neck webbing was found in 35% of the X(M) (n = 133) and 22% of the X(P) (n = 50) groups (P = 0.11). Renal anomalies were present in 24% of X(M) and 25% of X(P) groups (P = 0.9). Bicuspid aortic valve was found in 26% of X(M) and 24% of X(P) groups (P = 0.83), and any cardiovascular anomaly (abnormal aortic valve, aortic coarctation, elongated transverse aortic arch, anomalous pulmonary venous connection, left superior vena cava) affected 55% of X(M) and 52% of X(P) groups. Thus, we found no evidence for X-linked genomic imprinting effects on stature or lymphatic, renal or cardiovascular development in TS. Our sample size was sufficient to exclude such effects within 95% confidence limits. We did demonstrate a selective maternal effect on final stature that was independent of X-chromosome origin, suggesting potential autosomal imprinting effects on growth revealed by X monosomy.

Single-minded 1 (SIM1) mutations are associated with obesity in mice and humans. Haploinsufficiency of mouse Sim1 causes hyperphagic obesity with increased linear growth and enhanced sensitivity to a high-fat diet, a phenotype similar to that of agouti yellow and melanocortin 4 receptor knockout mice. To investigate the effects of increased Sim1 dosage, we generated transgenic mice that overexpress human SIM1 and examined their phenotype. Compared with wild-type mice, SIM1 transgenic mice had no obvious phenotype on a low-fat chow diet but were resistant to diet-induced obesity on a high-fat diet due to reduced food intake with no change in energy expenditure. The SIM1 transgene also completely rescued the hyperphagia and partially rescued the obesity of agouti yellow mice, in which melanocortin signaling is abrogated. Our results indicate that the melanocortin 4 receptor signals through Sim1 or its transcriptional targets in controlling food intake but not energy expenditure.

Single-minded 1 (SIM1) is one of only six genes implicated in human monogenic obesity. Haploinsufficiency of this hypothalamic transcription factor is associated with hyperphagic obesity and increased linear growth in both humans and mice. Additionally, Sim1 heterozygous mice show enhanced hyperphagia and obesity in response to a high-fat diet. Thus the phenotype of Sim1 haploinsufficiency is similar to that of agouti yellow (Ay), and melanocortin 4 receptor (Mc4r) knockout mice, both of which are defective in hypothalamic melanocortin signaling. Sim1 and Mc4r are both expressed in the paraventricular nucleus (PVN). Here we report that Sim1 heterozygous mice, which have normal energy expenditure, are hyperphagic despite having elevated hypothalamic proopiomelanocortin (Pomc) expression. In response to the melanocortin agonist melanotan-2 (MTII) they exhibit a blunted suppression of feeding yet increase their energy expenditure normally. They also fail to activate PVN neurons in response to the drug at a dose that induces robust c-Fos expression in a subset of Sim1 PVN neurons in wild-type mice. The resistance to melanocortin signaling in Sim1 heterozygotes is not due to a reduced number of Sim1 neurons in the PVN. Hypothalamic Sim1 gene expression is induced by leptin and MTII treatment. Our results demonstrate that Sim1 heterozygotes are resistant to hypothalamic melanocortin signaling and suggest that Sim1-expressing PVN neurons regulate feeding, but not energy expenditure, in response to melanocortin signaling.

Background: Turner syndrome (TS) results from the loss of part or all of one X chromosome in females. It can result in short stature, various dysmorphic findings, and difficulties with psychosocial adjustment. Girls with TS have previously been found to exhibit increased levels of hyperactivity and inattention. However, no studies have assessed whether individuals with TS meet strict (DSM-IV) criteria for attention-deficit/hyperactivity disorder (ADHD)., Objective: We looked at the prevalence of ADHD in girls with TS and evaluated the contribution of imprinting on cognitive performance (IQ) and ADHD., Methods: We tested 50 girls with TS for ADHD, IQ, academic performance, and parental origin of the X chromosome., Results: We report an 18-fold increase in the prevalence of ADHD in girls with TS (24%) compared with girls in the general population (1.3%) (p < .01) and a 4.8 fold increase when compared with boys and girls in the general population (5%) (p < .05). In contrast to previous reports, our molecular studies in females with 45,X also showed no association between IQ scores and the parental origin of the intact X chromosome., Conclusions: We find an increased prevalence of ADHD in girls with TS but no evidence for imprinting effects for cognitive performance.

BACKGROUND: The 13q-deletion syndrome causes human congenital birth defects due to the loss of regions of one long arm of human chromosome 13. A distal critical region for severe genitourinary and anorectal birth defects in the region of 13q32.2-34 has been suggested; we sought to narrow this critical region. METHODS: From patients with karyotypes revealing haploinsufficiency for distal chromosome 13q and their parents, peripheral blood was obtained and lymphocytes were immortalized for DNA isolation. Genetic and molecular cytogenetic methods were used to map deletions. Patient and parental samples were genotyped with a panel of 20 microsatellite markers spanning 13q31.3 qter and deletions identified by loss of heterozygosity. Deletions were also mapped using a panel of 35 BAC clones from the same region as probes for fluorescence in-situ hybridization on patient lymphoblastoid metaphase preparations. The data were synthesized and a deletion map defining the critical region was generated. RESULTS: Eight patients with known deletions around 13q32qter and their parents were analyzed, and categorized into three groups: three patients with anorectal and genitourinary anomalies (hypospadias, penoscrotal transposition), four male patients without anorectal and genitourinary anomalies, and one XY patient with ambiguous genitalia without anorectal anomalies. We mapped the critical region for anorectal and genitourinary anomalies to a approximately 9.5-Mb interval of 13q33.3-q34 delineated by markers D13S280-D13S285; this spans approximately 8% of the chromosome and contains 20 annotated genes CONCLUSION: The critical region of chromosome 13q mediating genitourinary/anorectal anomalies has been mapped, and will be narrowed by additional patients and further mapping. Identification of the gene(s) mediating these syndromic genitourinary defects should further our knowledge of molecular mediators of non-syndromic hypospadias, penoscrotal transposition and anorectal malformations.

Objective: To evaluate the growth disorder and phenotype in prepubertal children with Leri-Weill dyschondrosteosis (LWD), a dominantly inherited skeletal dysplasia, and to compare the findings from girls with Turner syndrome (TS)., Study Design: We studied the auxologic and phenotypic characteristics in 34 prepubertal LWD subjects (ages 1 to 10 years; 20 girls, 14 boys) with confirmed short stature homeobox-containing gene (SHOX) abnormalities. For comparative purposes, we evaluated similar physical and growth parameters in 76 girls with TS (ages 1 to 19 years) and 24 girls with LWD (ages 1 to 15 years) by using data collected from the postmarketing observational study, GeNeSIS., Results: In the clinic sample LWD subjects, height standard deviation score ranged from -5.5 to +0.1 (-2.3 +/- 1.3, girls and -1.8 +/- 0.6, boys). Wrist changes related to Madelung deformity were present in 18 of 34 (53%) LWD subjects. In comparing the LWD and TS populations in the GeNeSIS sample, Madelung deformity, increased carrying angle, and scoliosis were more prevalent in the LWD population, whereas high arched palate was similarly prevalent in the two populations., Conclusions: Short stature is common in both LWD (girls and boys) and TS (girls). Clinical clues to the diagnosis of SHOX haploinsufficiency in childhood include short stature, short limbs, wrist changes, and tibial bowing.

Context: Klinefelter syndrome (KS; 47,XXY karyotype and variants) is characterized by tall stature and testicular failure, with marked variation in severity of the phenotype. Previous studies have proposed that genetic factors including mosaicism, parental origin of the supernumerary X-chromosome, skewed X inactivation, and androgen receptor (AR) polyglutamine repeat length may contribute to phenotypic variability in KS., Objective: The objective of this study was to investigate the roles of these genetic factors in the variability of the KS phenotype., Design: This was a cross-sectional study., Setting: The study was performed at a pediatric endocrinology referral clinic., Patients: Thirty-five KS boys and men, aged 0.1-39 yr, were studied., Interventions: There were no interventions., Main Outcome Measures: Auxological measurements, biological indices of testicular function, and clinical assessment of muscle tone were the main outcome measures. Genetic studies included karyotyping to detect mosaicism, genotyping of microsatellite markers to determine parental origin of the supernumerary X-chromosome, and genotyping and methylation studies to measure AR polyglutamine (AR CAGn) repeat length and X inactivation ratio., Results: The only genetic factor that significantly influenced the KS phenotype was the AR CAGn repeat length, which was inversely correlated with penile length, a biological indicator of early androgen action. Mosaicism, imprinting, and skewed X inactivation did not account for the variability of the KS phenotype., Conclusions: Normal genetic variation in the AR coding sequence may be clinically significant in the setting of early testicular failure and subnormal circulating testosterone levels, as occur in KS.

Three siblings, two boys and one girl, presented with pigmentary abnormalities. The brothers, ages 11 and 6 years, had diffuse reticulate macular hyperpigmentation with onset in early childhood. In addition, these boys had hypohydrosis, coarse hair with an upswept frontal hairline, failure to thrive, and chronic pulmonary disease. The older boy also had corneal dystrophy and marked photophobia. A punch biopsy specimen from the 11-year-old showed melanophages and necrotic keratinocytes. Stains for amyloid were negative. The sister, age 2 years, had congenital linear hyperpigmented patches involving the intertrigenous areas, but was otherwise normal. The clinical findings of these children were consistent with X-linked reticulate pigmentary disorder with systemic manifestations. We present a summary of the clinical manifestations of this rare disorder and discuss efforts to identify the causative gene.

Haploinsufficiency of the transcription factor gene Sim1 has been previously implicated in hyperphagic obesity in humans and mice. To investigate the relation between Sim1 dosage and hyperphagia, we generated sim1-knockout mice and studied their growth and feeding behavior. Heterozygous mice weaned on standard chow consumed 14% more food per day than controls and developed obesity, hyperinsulinemia, and hyperleptinemia. The sim1 heterozygous mice were also significantly longer than controls. Heterozygous animals had modestly increased feeding efficiency, suggesting reduced energy expenditure, but voluntary wheel-running activity did not differ significantly between the two groups. We studied the effect of dietary fat on the feeding behavior of heterozygous sim1 mutant mice. The tempo and severity of weight gain were much greater in animals weaned on a high-fat diet. When acutely challenged with increased dietary fat, sim1 heterozygous mice weaned on the chow diet markedly increased their food consumption and caloric intake, whereas control mice reduced the mass of food they consumed and maintained approximately isocaloric intake. In wild-type adult mice, we detected Sim1 expression in the paraventricular and supraoptic nuclei, as previously reported in neonates, as well as in the amygdala and lateral hypothalamus, all regions implicated in feeding behavior. Our results indicate that Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat and likely plays a physiological role in the regulation of energy balance.

We studied two children with combined genetic skeletal disorders. Both had Leri-Weill dyschondrosteosis (LWD); one also had achondroplasia and the other had hypochondroplasia. Both had severe short stature and evidence of rhizomelia and mesomelia as well as other phenotypic features of their individual genetic disorders. Achondroplasia was due to the G380R FGF3R mutation and hypochondroplasia to a N540K mutation in the same gene. The patient with hypochondroplasia had a heterozygous SHOX deletion; no SHOX mutation was identified in the child with achondroplasia. The phenotypes of combined LWD and achondroplasia or hypochondroplasia appeared to be less than additive, suggesting that SHOX and FGFR3 act on overlapping pathways of bone growth and development., (Copyright 2002 Wiley-Liss, Inc.)

The SHOX (short-stature homeobox-containing) gene encodes isoforms of a homeodomain transcription factor important in human limb development. SHOX haploinsufficiency has been implicated in three human growth disorders: Turner syndrome, idiopathic short stature, and Leri-Weill dyschondrosteosis. Langer mesomelic dysplasia is thought to be the homozygous form of dyschondrosteosis. However, complete SHOX deficiency has not been demonstrated for any postnatal patient with the classic Langer phenotype. We studied four adults and one child with Langer mesomelic dysplasia. SHOX abnormalities were detected in all five probands. One was a homozygote or hemizygote and two were compound heterozygotes. The homozygous or hemizygous mutation was in exon 6a, implying that the SHOXa isoform is essential for normal skeletal development. These findings confirm clinical inferences that Langer mesomelic dysplasia is the homozygous form of Leri-Weill dyschondrosteosis and add to our understanding of genotype/phenotype relationships in SHOX deficiency disorders., (Copyright 2002 Wiley-Liss, Inc.)

Balanced translocations with breakpoints in a critical region of the X chromosome, Xq13-->q26, are associated with premature ovarian failure (POF). Translocations may cause POF either by affecting expression of specific X-linked genes essential for maintenance of normal ovarian function or by a chromosomal effect such as inhibition of meiotic pairing or altered X inactivation. We previously mapped seven Xq translocation breakpoints associated with POF to approximately 75-kb intervals. One translocation disrupted an aminopeptidase gene, XPNPEP2. We have now refined the map location of the remaining six breakpoints with respect to known genes and transcription units predicted from the draft human genome sequence. Only one of the six breakpoints disrupts a gene, DACH2, the human ortholog of a mouse gene expressed in embryonic nervous tissue, sensory organs, and limbs. DACH2 has no obvious relationship to ovarian function. The other five breakpoints fall in apparently intragenic regions. Our results are most consistent with models for POF associated with X;autosome translocations that involve generalized chromosome effects., (Copyright 2002 S. Karger AG, Basel)