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Dyslexia (reading and spelling disability) is one of the most frequently diagnosed disorders in childhood. Twin studies of dyslexia have indicated that deficits in spelling are substantially heritable and that the heritability of spelling deficits is higher than the heritability of reading deficits. We conducted a linkage study for spelling disability in seven multiplex families from Germany. Following previously reported linkage findings of components of dyslexia to chromosome 6p21-p22 and 15q21, we genotyped 26 microsatellite markers covering all of chromosome 6, and 13 microsatellite markers covering all of chromosome 15. While the chromosome 6 data were negative, results from chromosome 15 markers supported a locus on 15q21. The highest two-point LOD score was 1.26 with marker D15S143 at theta = 0. A multipoint LOD score of 1.78 (p = 0.0042) was achieved with a maximum at D15S132. Thus, our results provide independent support for a dyslexia gene on the long arm of chromosome 15. [ABSTRACT FROM AUTHOR]

Background: Perivascular space (PVS) enlargement in ageing and Alzheimer's disease (AD) and the drivers of such a structural change in humans require longitudinal investigation. Elucidating the effects of demographic factors, hypertension, cerebrovascular dysfunction, and AD pathology on PVS dynamics could inform the role of PVS in brain health function as well as the complex pathophysiology of AD., Methods: We studied PVS in centrum semiovale (CSO) and basal ganglia (BG) computationally over three to four annual visits in 503 participants (255 females; mean age  = 70.78 ± 5.78) of the ongoing observational multicentre "DZNE Longitudinal Cognitive Impairment and Dementia Study" (DELCODE) cohort. We analysed data from subjects who were cognitively unimpaired (n = 401), had amnestic mild cognitive impairment (n = 71), or had AD (n = 31). We used linear mixed-effects modelling to test for changes of PVS volumes in relation to cross-sectional and longitudinal age, as well as sex, years of education, hypertension, white matter hyperintensities, AD diagnosis, and cerebrospinal-fluid-derived amyloid (A) and tau (T) status (available for 46.71%; A-T-/A + T-/A + T + n = 143/48/39)., Results: PVS volumes increased significantly over follow-ups (CSO: B = 0.03 [0.02, 0.05], p < 0.001; BG: B = 0.05 [0.03, 0.07], p < 0.001). PVS enlargement rates varied substantially across subjects and depended on the participant's age, white matter hyperintensities volumes, and amyloid and tau status. PVS volumes were higher across elderly participants, regardless of region of interest (CSO: B = 0.12 [0.02, 0.21], p = 0.017; BG: B = 0.19 [0.09, 0.28], p < 0.001). Faster BG-PVS enlargement related to lower baseline white matter hyperintensities volumes (ρ spearman  = -0.17, p FDR  = 0.001) and was more pronounced in individuals who presented with combined amyloid and tau positivity versus negativity (A + T +  > A-T-, p FDR  = 0.004) or who were amyloid positive but tau negative (A + T +  > A + T-, p FDR  = 0.07). CSO-PVS volumes increased at a faster rate with amyloid positivity as compared to amyloid negativity (A + T-/A + T +  > A-T-, p FDR  = 0.021)., Conclusion: Our longitudinal evidence supports the relevance of PVS enlargement in presumably healthy ageing as well as in AD pathology. We further discuss the region-specific involvement of white matter hyperintensities and neurotoxic waste accumulation in PVS enlargement and the possibility of additional factors contributing to PVS progression. A comprehensive understanding of PVS dynamics could facilitate the understanding of pathological cascades and might inform targeted treatment strategies., Trial Registration: German Clinical Trials Register DRKS00007966. Registered 04.05.2015 - retrospectively registered, https://drks.de/search/en/trial/DRKS00007966 ., (© 2024. The Author(s).)

Background: Multiple system atrophy (MSA), an atypical parkinsonian syndrome, is a rapidly progressive neurodegenerative disease with currently no established fluid biomarkers available. MSA is characterized by an oligodendroglial α-synucleinopathy, progressive neuronal cell loss and concomitant astrocytosis. Here, we investigate glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) as fluid biomarkers for differential diagnosis, assessment of clinical disease severity and prediction of disease progression in MSA., Methods: GFAP and NfL levels were analyzed in plasma and CSF samples of 47 MSA patients as well as 24 Parkinson's disease (PD) and 25 healthy controls (HC) as reference cohorts. In MSA, biomarker levels were correlated to baseline and longitudinal clinical disease severity (UMSARS scores)., Results: In MSA, GFAP levels in CSF and plasma predicted baseline clinical disease severity as indicated by UMSARS scores, while NfL levels predicted clinical disease progression as indicated by longitudinal changes in UMSARS scores. Cross-sectionally, NfL levels in CSF and plasma were significantly elevated in MSA compared to both PD and HC. Receiver operating curves (ROC) indicated high diagnostic accuracy of NfL for distinguishing MSA from PD (CSF: AUC = 0.97, 95% CI 0.90-1.00; plasma: AUC = 0.90, 95% CI 0.81-1.00)., Discussion: In MSA, GFAP shows promise as novel biomarker for assessing current clinical disease severity, while NfL might serve as biomarker for prediction of disease progression and differential diagnosis of MSA against PD., (© 2024. The Author(s).)

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological ageing. It is not known whether divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± standard deviation, age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (n = 342), mild cognitive impairment (n = 118) or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid Alzheimer's disease biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5) as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test whether baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and mild cognitive impairment conversion rates of cognitively unimpaired participants and those with subjective cognitive decline. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy initially affected the medial temporal lobes, followed by further temporal regions and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological Alzheimer's disease biomarker levels, APOE ε4 carriership and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe, with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive Alzheimer's disease biomarkers and was associated with more generalized cognitive impairment. Limbic-predominant atrophy, in all participants and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of mild cognitive impairment conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, at both the subject and the group level, was excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for Alzheimer's disease in applied settings. The implementation of atrophy subtype- and stage-specific end points might increase the statistical power of pharmacological trials targeting early Alzheimer's disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials., (© 2024. The Author(s).)

Background and Objectives: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer disease (AD) biomarkers, cognitive decline, and clinical progression to mild cognitive impairment (MCI)., Methods: This study included patients with clinical SCD and SCD-free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer's Disease neuropsychological assessment battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-β (Aβ)42/Aβ40, phosphorylated tau (p-tau 181 ) , total tau and Aβ42/p-tau 181 levels, longitudinal cognitive composite trajectories, and risk of clinical progression to incident MCI (follow-up M ± SD : 40.6 ± 23.7 months). In addition, we explored group differences between SCD and HC in those without MNPD., Results: In our sample (N = 672, mean age: 70.7 ± 5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline, and a higher risk of progression to incident MCI (HR: 4.07, 95% CI 2.46-6.74) compared with SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95% CI 38.5-75.4) and a negative predictive value of 86.0% (95% CI 81.9-90.1) for the progression of SCD to MCI within 3 years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared with HC participants without MNPD (n = 215; HR: 4.09, 95% CI 2.07-8.09), while AD biomarker levels did not differ significantly between these groups., Discussion: Our results suggest that MNPD are a risk factor for AD-related clinical progression in cognitively normal patients seeking medical counseling because of SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Purpose: The Scale for Assessment and Rating of Ataxia (SARA) is a widely used clinical scale. The objective was to study the age dependence of SARA in healthy adults and to define age-specific cut-off values to differentiate healthy from ataxic individuals., Methods: Data from 390 healthy individuals and 119 spinocerebellar ataxia patients were analyzed. SARA scores were mapped on functional SARA (fSARA). Age-adjusted cut-off values were determined by receiver operating characteristic curve analysis., Results: The cut-off value was 3 for SARA and 1.5 for fSARA. Older patients had higher SARA cut-off values (4.5 for 60-69 years and 6.5 for 70-79 years). Age-adjusted cut-off values for fSARA are 1 for 18-29, 30-39 and 50-59 years, 2 for 40-49 and 60-69 years and 3 for 70-79 years. Sensitivity and specificity were higher for SARA than for fSARA., Conclusion: In this study, age-dependent cut-off values were defined for SARA and fSARA. The results may be relevant for the design of future preventive trials in spinocerebellar ataxias that use conversion to ataxia as an outcome., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Measures of step variability and body sway during gait have shown to correlate with clinical ataxia severity in several cross-sectional studies. However, to serve as a valid progression biomarker, these gait measures have to prove their sensitivity to robustly capture longitudinal change, ideally within short time frames (eg, 1 year). We present the first multicenter longitudinal gait analysis study in spinocerebellar ataxias. We performed a combined cross-sectional (n = 28) and longitudinal (1-year interval, n = 17) analysis in Spinocerebellar Ataxia type 3 subjects (including seven preataxic mutation carriers). Longitudinal analysis showed significant change in gait measures between baseline and 1-year follow-up, with high effect sizes (stride length variability: P = 0.01, effect size r prb  = 0.66; lateral sway: P = 0.007, r prb  = 0.73). Sample size estimation for lateral sway indicates a required cohort size of n = 43 for detecting a 50% reduction of natural progression, compared with n = 240 for the clinical ataxia score Scale for the Assessment and Rating of Ataxia (SARA). These measures thus present promising motor biomarkers for upcoming interventional studies. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Rivastigmine is an acetylcholine esterase inhibitor which is commonly used as therapy for dementia in Alzheimer's disease and Parkinson's disease (PD). Recently, a randomized controlled trial demonstrated a positive effect of rivastigmine on gait function in nondemented PD patients. Disturbed gait is a shared hallmark of PD and ataxias., Objectives: We hypothesized that the effect of rivastigmine could be translated to spinocerebellar ataxia (SCA) improving gait function., Method: Five patients with SCA type 3 were treated with transdermal rivastigmine for 8 weeks. The patients were monitored using the Scale for the Assessment and Rating of Ataxia (SARA) and an electronic walkway system (GAITRite®)., Results: Gait function was not changed by treatment, but 4 patients who continued treatment for 8 weeks showed improved coordination of extremities. The SARA sum score, which was 7.6 ± 2.2 at baseline, had dropped by 1.5 ± 1.9 after 4 weeks and by 2.1 ± 1.4 after 8 weeks., Conclusions: Contrary to our hypothesis, we observed no improvement of gait parameters as assessed by SARA and GAIT-Rite®, but coordination abilities were improved. Rivastigmine was well tolerated, but known side effects of rivastigmine, such as deterioration of asthma, may appear. Further trials in larger cohorts are needed to confirm our findings., (© 2020 S. Karger AG, Basel.)

Multiple system atrophy (MSA) and sporadic, non-mendelian Parkinson's disease (PD) are progressive neurodegenerative disorders with overlapping clinical symptoms and pathology. The etiology of both disorders is unknown, and complex combinations of multiple susceptibility genes and environmental factors are thought to be involved. Both disorders are characterized by ubiquitous alpha-synuclein aggregates in distinct regions and cell types of the central nervous system. In PD, alpha-synuclein-positive aggregates appear to be largely neuronal while in MSA oligodendroglial inclusions prevail. In PD patients, the alpha-synuclein pathology is thought to evolve in a rather regular pattern, starting in the brainstem and olfactory bulb and extending gradually onto the substantia nigra and ultimately the cerebral cortex while the cerebellum is largely spared. MSA pathology has not been graded in a similar way yet; neuropathological analyses revealed neurodegeneration and gliosis primarily in the brainstem, midbrain and basal ganglia and the cerebellum, while the cortex is largely spared. To identify disease-specific transcriptional patterns in MSA, we chose CNS regions differentially affected in MSA and PD for comparative gene expression profiling: putamen, cerebellum and occipital cortex. Four genes were regulated in both MSA and PD putamen and twelve in MSA and PD cerebellum. Regulated transcripts were validated using real-time quantitative RT-PCR, and immunohistochemistry was performed for the most significantly downregulated transcripts in MSA and PD putamen, GPR86 and RGS14, associated with G protein signaling and transcriptional regulation.

Spinocerebellar ataxia type 3 (SCA3) is a late-onset neurodegenerative disorder caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that mutant ataxin-3 causes upregulation of inflammatory genes in transgenic SCA3 cell lines and human SCA3 pontine neurons. We report here a complex pattern of transcriptional changes by microarray gene expression profiling and Northern blot analysis in a SCA3 cell model. Twenty-three differentially expressed genes involved in inflammatory reactions, nuclear transcription, and cell surface-associated processes were identified. The identified corresponding proteins were analyzed by immunohistochemistry in human disease and control brain tissue to evaluate their implication in SCA3 pathogenesis. In addition to several inflammatory mediators upregulated in mutant ataxin-3 expressing cell lines and pontine neurons of SCA3 patients, we identified a profound repression of genes encoding cell surface-associated proteins in cells overexpressing normal ataxin-3. Correspondingly, these genes were upregulated in mutant ataxin-3 expressing cell lines and in pontine neurons of SCA3 patients. These findings identify for the first time target genes transcriptionally regulated by normal ataxin-3 and support the hypothesis that both loss of normal ataxin-3 and gain of function through protein-protein interacting properties of mutant ataxin-3 contribute to SCA3 pathogenesis.

Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine disorder caused by a CAG repeat expansion in the coding region of a gene encoding ataxin-3. To study putative alterations of gene expression induced by expanded ataxin-3, we performed PCR-based cDNA subtractive hybridization in a cell culture model of SCA3. In rat mesencephalic CSM14.1 cells stably expressing expanded ataxin-3, we found a significant upregulation of mRNAs encoding the endopeptidase matrix metalloproteinase 2 (MMP-2), the transmembrane protein amyloid precursor protein, the interleukin-1 receptor-related Fos-inducible transcript, and the cytokine stromal cell-derived factor 1alpha (SDF1alpha). Immunohistochemical studies of the corresponding or associated proteins in human SCA3 brain tissue confirmed these findings, showing increased expression of MMP-2 and amyloid beta-protein (Abeta) in pontine neurons containing nuclear inclusions. In addition, extracellular Abeta-immunoreactive deposits were detected in human SCA3 pons. Furthermore, pontine neurons of SCA3 brains strongly expressed the antiinflammatory interleukin-1 receptor antagonist, the proinflammatory cytokine interleukin-1beta, and the proinflammatory chemokine SDF1. Finally, increased numbers of reactive astrocytes and activated microglial cells were found in SCA3 pons. These results suggest that inflammatory processes are involved in the pathogenesis of SCA3.

Background: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise., Methods and Results: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected., Conclusions: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of central nervous functions by activating multiple 5-HT receptor subtypes. A possible irregularity of serotonergic neurotransmission has been implicated in a variety of neuropsychiatric diseases. In the present study, we performed a systematic mutation scan of the complete coding region and splice junctions of the 5-HT(6) receptor gene to explore the contribution of this gene to the development of bipolar affective disorder and schizophrenia. Investigating 137 unrelated individuals (including 45 bipolar affective patients, 46 schizophrenic patients, and 46 unrelated controls), we identified six single base substitutions (126G/T, 267C/T, 873+30C/T, 873+128A/C, 1128G/C, 1376T/G). Comparing frequencies between patients and controls, we observed a significant overrepresentation of the 267C allele among bipolar patients (P=0. 023 not corrected for multiple testing). This finding was followed up in an independent sample of 105 bipolar family trios using a family-based association design. Fifty-one transmissions could be examined. In 30 cases allele 267C and in 21 cases allele 267T were transmitted to the affected offspring. Although this result was far from statistical significance (transmission disequilibrium test=1.59, P=0.208), the limited number of possible transmissions may have prevented detection of smaller effects. Our preliminary data suggest that bipolar affective disorder may be associated with variation in the 5-HT(6) gene. It will be important to extend the present analysis to larger samples. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:217-221, 2000., (Copyright 2000 Wiley-Liss, Inc.)

Complete or partial congenital absence of hair (congenital alopecia) may occur isolated or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal recessive mode of inheritance (MIM 203655). We have previously mapped the gene for autosomal recessive congenital alopecia in a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia) to a 15 cM region on chromosome 8p21-22. Here we report the cloning and characterization of the human homologue of the mouse hairless gene and show that it is located in the critical region on chromosome 8p21-22. Determining the exon-intron structure allowed detailed mutational analysis of DNA samples of patients with universal congenital alopecia. We detected a homozygous missense mutation in the Pakistani family and a homozygous splice donor mutation in a family from Oman. In addition, we show that the human hairless gene undergoes alternative splicing and that at least two isoforms generated by alternative usage of exon 17 are found in human tissues. Interestingly, the isoform containing exon 17 is the predominantly expressed isoform in all tissues but skin, where exclusive expression of the shorter isoform was observed. We speculate that this tissue-specific difference in the proportion of hairless transcripts lacking exon 17 sequences could contribute to the tissue-specific disease phenotype observed in individuals with isolated congenital alopecia.

Complete or partial congenital absence of hair (congenital alopecia) may occur either in isolation or with associated defects. The majority of families with isolated congenital alopecia has been reported to follow an autosomal-recessive mode of inheritance (MIM 203655). As yet, no gene has been linked to isolated congenital alopecia, nor has linkage been established to a specific region of the genome. In an attempt to map the gene for the autosomal recessive form of the disorder, we have performed genetic linkage analysis on a large inbred Pakistani family in which affected persons show complete absence of hair development (universal congenital alopecia). We have analyzed individuals of this family, using >175 microsatellite polymorphic markers of the human genome. A maximum LOD score of 7.90 at a recombination fraction of 0 has been obtained with locus D8S258. Haplotype analysis of recombination events localized the disease to a 15-cM region between marker loci D8S261 and D8S1771. We have thus mapped the gene for this hereditary form of isolated congenital alopecia to a locus on chromosome 8p21-22 (ALUNC [alopecia universalis congenitalis]). This will aid future identification of the responsible gene, which will be extremely useful for the understanding of the biochemistry of hair development.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter that mediates a wide range of sensory, motor, and cortical functions by activating multiple 5-HT receptor subtypes. In the present study we performed a systematic mutation scan of the complete coding region of the 5-HT5A receptor to explore its variability in the general population. Investigating 46 unrelated healthy subjects by single-strand conformation analysis no sequence changes of likely functional relevance were observed. The detection of a frequent G-->C substitution at position -19 was used for fine scale linkage mapping of the 5-HT5A gene. Employing a polymerase-chain-reaction based assay we genotyped 7 CEPH families (Centre d'Etude du Polymorphisme Humaine) and mapped the receptor to genetic markers on chromosome 7q34-q36.