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Sub‐heading Compound hemizygous variants in SERPINA7 gene. Background Thyroxine‐binding globulin (TBG) is encoded by SERPINA7 (OMIM. 314200) which is located on Xq22.3. SERPINA7 variants caused TBG deficiency which does not require treatment, but the decreased thyroxine may be misdiagnosed as hypothyroidism. We discovered some variants of TBG caused by alterations that differ from previously reported. Materials and Methods In this study, we enrolled 32 subjects from 10 families and sequenced the SERPINA7 genes of TBG‐deficient subjects. Then, variants were analyzed to assess their effect on TBG expression and secretion. Bioinformatics database, protein structure, and dynamics simulation were used to evaluate the deleterious effects. Finally, we identified 2 novel and 4 known variants, and found 26 of 30 subjects carried the p.L303F. The DynaMut predictions indicated the variants (p.E91K, p.I92T, p.R294C, and p.L303F) exhibited decreased stability. Conclusion Analyses revealed the p.L303F change the protein stability and flexibility, and it had an impact on the function of TBG, but when coexisted with other variants it might change the conformational structure of the protein and aggravate the damage to the protein. We speculated that the existence of a higher number of variants resulted in lower TBG secretion., The p.L303F that previouly identified as a variant had an impact on the function and stability of TBG, and when coexisted with other variants it might change the conformational structure of the protein and aggravate the damage to the protein. The existence of a higher number of variants resulted in lower TBG secretion.

Background Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses. Methods Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next‐generation sequencing was used to screen for suspected pathogenic variants. Family co‐segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance. Results All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation‐induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton's tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins. Conclusion Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper‐IgM syndrome type 2 (HIGM2) and X‐linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland., In this paper, comprehensive clinical characteristics of the PIDDs patients are recorded, which will give more evidence for the diagnosis of the two diseases. Two novel mutations have never been reported before were identified, which will enrich the worldwide spectrum of HIGM2 and XLA. Moreover, this is the first report of HIGM2 caused by AICDA deficiency in the Chinese mainland cohorts, which will set a good example for similar cases in the future.

Background Psoriasis is a chronic inflammatory dermatosis with complex genetic basis supported by family investigation. Renal involvement in psoriasis is sparsely studied and its pathogenesis is still unclear. Methods and Results We describe the case of a 7‐year‐old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. His mother had a long history of psoriasis without abnormal urinalysis records. The case showed non‐nephrotic range proteinuria, microscopic hematuria without any other abnormal results including renal function, complement cascade, and ultrasound. Renal pathological demonstrated the diagnosis of C3 glomerulonephritis (C3GN) showing mesangial proliferative glomerulonephritis with C3 staining only, effacement of podocyte process and intramembranous electron dense deposit by electric microscopy. Parent‐child trio WES performed to screening the common variants of psoriasis susceptibility locus and also the rare variants associated with C3GN. We identified a missense single nucleotide polymorphism of CARD14 (*607211, rs34367357, p.Val585Ile) carried by the proband and his mother. Meta‐analysis proved the association of rs34367357 and psoriasis (p = 0.006, OR = 1.23). A hemizygouse mutation of CLCN5 (*300008, c.1904A＞G,p.Asn635Ser) was identified for diagnosis of Dent disease (*300009). Conclusion The case highlights the genetic study is necessary to facilitate disease differentiation in new onset of nephropathy with psoriasis in children., A case of a 7‐year old boy presented new onset of nephropathy two weeks after a flare‐up of psoriasis. Pathological findings and genetic study identified the diagnosis of C3 glomerulonephritis with psoriasis accompanied by Dent disease.

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X-linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21-year-old patient with fatal Epstein-Barr virus infection-associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.

Aims Islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to β-cell failure in type 2 diabetes, cultured and transplanted islets. We previously showed that biosynthetic hIAPP aggregates induce β-cell Fas upregulation and activation of the Fas apoptotic pathway. We used cultured human and hIAPP-expressing mouse islets to investigate: (1) the role of interleukin-1β (IL-1β) in amyloid-induced Fas upregulation; and (2) the effects of IL-1β-induced β-cell dysfunction on pro-islet amyloid polypeptide (proIAPP) processing and amyloid formation. Research Design and Methods Human and h IAPP -expressing mouse islets were cultured to form amyloid without or with the IL-1 receptor antagonist (IL-1Ra) anakinra, in the presence or absence of recombinant IL-1β. Human islets in which amyloid formation was prevented (amyloid inhibitor or Ad-prohIAPP-siRNA) were cultured similarly. β-cell function, apoptosis, Fas expression, caspase-8 activation, islet IL-1β, β-cell area, β-/α-cell ratio, amyloid formation, and (pro)IAPP forms were assessed. Results hIAPP aggregates were found to increase IL-1β levels in cultured human islets that correlated with β-cell Fas upregulation, caspase-8 activation and apoptosis, all of which were reduced by IL-1Ra treatment or prevention of amyloid formation. Moreover, IL-1Ra improved culture-induced β-cell dysfunction and restored impaired proIAPP processing, leading to lower amyloid formation. IL-1β treatment potentiated impaired proIAPP processing and increased amyloid formation in cultured human and h IAPP -expressing mouse islets, which were prevented by IL-1Ra. Conclusions IL-1β plays a dual role by: (1) mediating amyloid-induced Fas upregulation and β-cell apoptosis; (2) inducing impaired proIAPP processing thereby potentiating amyloid formation. Blocking IL-1β may provide a new strategy to preserve β cells in conditions associated with islet amyloid formation.

Background OFD1 has long been recognized as the gene implicated in the classic dysmorphology syndrome, oral‐facial‐digital syndrome type I (OFDSI). Over time, pathogenic variants in OFD1 were found to be associated with X‐linked intellectual disability, Joubert syndrome type 10 (JBTS10), Simpson‐Golabi‐Behmel syndrome type 2 (SGBS2), and retinitis pigmentosa. Recently, OFD1 pathogenic variants have been implicated in primary ciliary dyskinesia (PCD), a disorder of the motile cilia with a phenotype that includes recurrent oto‐sino‐pulmonary infections, situs abnormalities, and decreased fertility. Methods We describe three male patients with PCD who were found to have hemizygous pathogenic variants in OFD1, further supporting that PCD is part of a clinical spectrum of OFD1‐related disorders. In addition, we provide a review of the available clinical literature describing patients with OFD1 variants and highlight the phenotypic variability of OFD1‐related disease. Results Some individuals with hemizygous OFD1 variants have PCD, either apparently isolated or in combination with other features of OFD1‐related disorders. Conclusion As clinicians consider the presence or absence of conditions allelic at OFD1, PCD should be considered part of the spectrum of OFD1‐related disorders. Understanding the OFD1‐related disease spectrum may allow for more focused genetic testing and more timely management of treatable sequelae.

Currently 1582 HLA-DRB1 alleles have been identified in the IMGT/HLA database (v3.18). Among those alleles, more than 90% have incomplete allele sequences, which complicates the analysis of the functional relevance of polymorphism beyond exon 2. The polymorphic index of each individual exon of the currently known allele sequences, shows that polymorphism is present in all exons, albeit not equally abundant. Full-length HLA-DRB1 RNA sequencing identifies polymorphism of the complete coding region. Here we describe a hemizygous full-length RNA sequence-based typing (SBT) approach based on group-specific HLA-DRB1 amplification and subsequent sequencing. RNA full-length sequences can easily be accessed because of the short amplicon length (801 bp). The RNA-SBT approach was successfully validated on a panel of DRB1 alleles having fully known coding sequences according to the IMGT/HLA database, and cover all serological equivalents. Subsequently, the approach was applied on a panel of 54 alleles with incomplete allele sequences, resulting in full-length coding sequences and the identification of one new and one corrected allele. This study shows the universal applicability of the RNA-based sequencing approach to identify full-length coding sequences and to define the polymorphic content of HLA-DRB1 alleles.

Cutaneous leiomyoma is a benign skin tumor that originates from the smooth muscle, such as the arrector pili muscle of the hair follicles. Familial cases with multiple cutaneous leiomyomas exist, which typically show an autosomal dominant inheritance trait. Most patients with the disease are known to carry heterozygous germ line mutations in the fumarate hydratase (FH) gene and can be complicated by tumors in internal organs, especially uterine leiomyoma and renal cell cancer in high frequency. In this study, we identified a Japanese male patient with multiple cutaneous leiomyomas and found a novel heterozygous splice site mutation, c.738 + 2T>A, in the FH gene of the patient, which was unexpectedly inherited from his unaffected father. Further analysis demonstrated loss of heterozygosity in the tumor tissue, which resulted in a hemizygote state of the mutant allele. Expression studies with the tumor tissue showed that the mutation led to skipping of exon 5 at mRNA levels, which was predicted to cause an in-frame deletion of FH protein (p.Ser186_Gln246del). The protein structure analysis strongly suggested that the deletion would severely disrupt the conformation of the FH protein including the substrate-binding domain, and thus would severely affect the expression and the function. Our findings further disclose the molecular basis of multiple cutaneous leiomyomas and also provide precious information to the mutation carriers in the family for an early diagnosis of renal cell cancer in the future.

K-ras mutations are found in ~40% of human colorectal adenomas and carcinomas and contribute to colorectal tumour formation at an early stage. Wild-type K-ras has been reported to be deleted in some tumours, but the consequences of changes in wild-type K-ras copy number for experimental colorectal carcinogenesis have not been investigated. To characterize the effects of K-ras copy number changes on formation of carcinogen-induced colorectal neoplasms in mice, wild-type (K-ras(+/+) ) and heterozygous K-ras exon 1 knockout (K-ras(+/-) ) mice were given 10 weekly treatments of 1, 2-dimethylhydrazine (DMH) to induce colorectal tumours. Colorectal expression levels of K-ras 4A and 4B transcripts in K-ras(+/-) mice were ~50% decreased compared with K-ras(+/+) mice. One year after DMH treatment, survival of K-ras(+/-) mice decreased from 88 to 82% compared with wild-type mice. Colorectal adenomas significantly increased from 0.52 ± 0.15 in K-ras(+/+) mice to 0.87 ± 0.14 in K-ras(+/-) mice (mean ± SEM per mouse, P

Gain of function mutations of KIT are frequent in some human tumors, and are sensible to tyrosine kinase inhibitors. In most tumors, oncogenic mutations are heterozygous, however most in vitro data of KIT activation have been obtained with hemizygous mutation. This study aimed to investigate the maturation and activation of wild‐type (WT) and mutant (M) forms of KIT in hemizygous and heterozygous conditions. WT and two types of exon 11 deletions M forms of human KIT were expressed in NIH3T3 cell lines. Membrane expression of KIT was quantified by flow cytometry. Quantification of glycosylated forms of KIT and phosphorylated forms of AKT and ERK were performed by western blot. Simultaneous activation of WT KIT and treatment with endoplasmic reticulum (ER) inhibitors, tunicamycin or brefeldin A induced a complete inhibition of membrane expression of the 145 kDa form of KIT. By contrast activation or ER inhibitors alone, only partly inhibited this form. ER inhibitors also inhibited KIT activation‐dependent phosphorylation of AKT and ERK1/2. Brefeldin A induced a complete down regulation of the 145 kDa form in hemizygous M, and induced an intra‐cellular accumulation of the 125 kDa form in WT but not in hemizygous M. Heterozygous cells had glycosylation and response to ER inhibitors patterns more similar to WT than to hemizygous M. Phosphorylated AKT was reduced in hemizygous cells in comparison to WT KIT cells and heterozygous cells, and in the presence of brefeldin A in all cell lines. Effects of ER inhibitors are significantly different in hemizygous and heterozygous mutants. Differences in intra‐cellular trafficking of KIT forms result in differences in downstream signaling pathways, and activation of PI3K/AKT pathway appears to be tied to the presence of the mature 145 kDa form of KIT at the membrane surface.

BACKGROUND: Some 270 variants in the RHD gene have so far been identified. Of these, approximately 6% (n = 17) are small (≤20 bp) deletions occurring within the gene's coding sequence. Fourteen of these small deletions disrupted the reading frame of the RHD gene, resulting almost invariably in a D– phenotype. STUDY DESIGN AND METHODS: Two subjects who displayed D phenotype ambiguity or a genotype-phenotype discrepancy were referred to our laboratory for RHD genetic analysis. Hemizygosity for the most common 70-kb RHD deletion was first determined in both subjects by long-range polymerase chain reaction (PCR) followed by PCR amplification and sequencing of all 10 exons of the RHD gene in the nondeleted allele individually. RESULTS: Two novel lesions in the RHD gene were identified on the nondeleted alleles, a 14-bp frameshifting deletion within Exon 1 (i.e., c.29_42delGGCGCTGCCTGCCC) and an 11-bp frameshifting deletion within Exon 3 (i.e., c.361_371delTTGTCGGTGCT), in Subjects 1 and 2, respectively. CONCLUSION: By reference to previously reported small deletions in the RHD gene, the 11-bp deletion in Exon 3 may be safely regarded as a bona fide D– variant. Although the association of the 14-bp deletion in Exon 1 with a weak D phenotype appears to be genuine, the underlying molecular mechanism still remains to be clarified. Evaluation of all known small RHD deletions points to slippage mutagenesis as the major underlying mutational mechanism.

A large Indian kindred in which the fragile X chromosome is segregating has been investigated in Cape Town. Eight male hemizygotes and four female heterozygotes were mentally retarded. There is suggestive evidence that one deceased male of reportedly normal intelligence may have been a hemizygote. The existence of the fragile X syndrome in a number of different ethnic groups supports the contention that the gene controlling the phenotype and the fragile site are the same, or at least overlap.

Exon 3 of DRB1 is known to be polymorphic, but thought to be conserved within allelic groups. This implies that exon 3 polymorphisms would not need to be considered in evolutionary studies or clinical settings when assessing immunogenicity of allelic mismatches in stem cell transplantation. To further assess this, we determined the sequences of DRB1 exon 3 by hemizygote amplification and direct sequencing on 55 selected DNA samples containing 42 DRB1 alleles for which no exon 3 sequence data were previously available. The data confirmed the high degree of overall sequence conservation. The DRB4- and DRB5-associated alleles were completely conserved within their DRB1 groups. However, it could be shown that exon 3 is more diverse than previously expected. Multiple allelic differences within each group of DRB3-associated DRB1 alleles were found, without identifying unique group-related sequence motifs differentiating between these groups. For DRB1*1402 and DRB1*1406, it could be shown that they originated from DRB1*0302. In several samples previously typed as DRB1*1401, a novel DRB1 allele was identified: DRB1*1454. Thus, from a clinical viewpoint, the availability of exon 3 sequence information may be useful for optimizing typing as well as matching strategies. Additionally, it will allow for more detailed evolutionary studies, further elucidating the origin of alleles and the mechanisms driving sequence diversification.

The macular mutant mouse is well known as a model of Menkes kinky hair disease (MKHD). This paper was presented to elucidate the pathogenesis of cerebellar Purkinje cell abnormalities of MKHD using this model mouse. The neuropathological changes on the Purkinje cells of this mouse were composed of somal sprout, somal spine, focal dendritic swelling, delay of arborization, abnormal mitochondria, abnormal inclusions, and low cytochrome c oxidase activity. Most of them were improved in the hemizygote treated with cupric chloride. These abnormal Purkinje cells were not distributed in a mosaic pattern in the cerebellum of the heterozygote. Hence, most of them resulted from copper deficiency in the cerebellum, and not from gene abnormality in the Purkinje cell.

A 34-year-old Japanese male had leg pain, edema of the legs, hypohidrosis, whorl-like opacities of the bilateral cornea, bilateral subcapsular cataracts, and chest discomfort on exercise. He had no characteristic angiokeratomas but did have telangiectases. The electrocardiogram revealed high voltage. The echocardiogram revealed mild mitral regurgitation. The alpha-galactosidase A activity in cultured lymphoblasts was deficient (0.5 nmol/h/mg protein). Electron microscopic examination of the skin revealed lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts. He had a G--> A transition at nucleotide 982 in the coding sequence of the alpha-galactosidase A gene which resulted in a glycine to arginine amino acid substitution at residue 328. His uncle also had leg pain, edema of the legs, hypohidrosis, and chest pain on exercise. He had no characteristic angiokeratomas but did have telangiectases. Cardiovascular examination revealed hypertrophic cardiomyopathy and stenoses of coronary arteries. Electron microscopic examination of the skin revealed lamellar cytoplasmic inclusions in the endothelial cells, pericytes, and fibroblasts.

This prospective study was performed to quantify glucose-6-phosphate dehydrogenase (G6PD) enzyme activity in deficient males and female heterozygotes. The methods used in the study were the fluorescent spot test, G6PD enzyme electrophoresis on cellulose acetate and quantitative assays. Forty-seven children who had been detected as spot screen deficient at birth were rescreened. Their first degree relatives were also included in the study. The mean enzyme activity of deficient males was 0.74 iu/g Hb (s.d. ± 0.8), of female heterozygotes was 6.5 iu/g Hb (s.d. ± 3.2) and of normal males was 12.1 iu/g Hb (s.d. ± 3.5). The mean activity in deficient males was 6.1% of normal males. Most (35 of 47) of these fell into class 2 in Beutler's classification of G6PD variants. This indicates a population which may be susceptible to favism. Female heterozygotes had an intermediate enzyme activity with a wide scatter. Using a cut off point of enzyme activity of below 9.0 iu/g Hb gave sensitivity and specificity respectively of 87% and 84% in detecting female heterozygotes. This group could be defined more accurately by combining quantitative assays with family studies.

SCT is a heterozygous genetic condition resulting from a single point mutation in the gene for the beta chain of hemoglobin (hemoglobin S, HbS), by which an encoded glutamate at position six is replaced with valine [1,2]. The prevalence of hemoglobin S in regions where it provides protection against malaria is a textbook example of balanced polymorphism and natural selection. G6PD is an enzyme which catalyzes the first step of the pentose phosphate pathway and supports the production of reduced glutathione, a major defense against oxidant stress in red blood cells. G6PD deficiency is an X-linked condition associated with damage to red blood cells and hemolysis in response to a variety of exposures, including infection, ingestion of fava beans, or exposure to certain chemicals or medications [3,4]. A number of epidemiological studies have associated SCT or G6PD deficiency with protection against malaria, in particular severe, life-threatening malaria in its cerebral form [5–9]. Protection by SCT and G6PD deficiency are usually thought to act independently, but no studies have reported whether the protective effects of these two conditions are synergistic, are neutrally additive, or interfere with one another. Here we report on the occurrence of uncomplicated and severe malaria in Malian children with SCT, the G6PD (A−) polymorphism, or both of these conditions together. Among children with SCT, the prevalence of severe versus uncomplicated malaria in children with the G6PD (A−) polymorphism was 12.2%. When evaluated by sex, this prevalence was 6.6% and 28.5% in hemizygous males and heterozygous females, respectively. These results raise the possibility that the heterozygous G6PD (A−) condition and sickle trait do not supplement and may even interfere with one another in their protection against severe malaria (OR = 15; 95CI 2.07–132.31; P = 0.003). SCT and G6PD (A−) deficiency are frequently cited examples of red blood cell polymorphisms that confer resistance to malaria. Despite the different hemoglobin and enzyme functions that are affected, these polymorphisms are prevalent at comparably high frequencies in many populations of Mali and other regions of Africa [10,11]. These distributions are generally thought to reflect natural selection from the protections that SCT and G6PD (A−) deficiency independently provide against severe malaria [12,13]. Results of the work presented here confirm the association of SCT with protection against severe malaria (P = 0.01). This result corroborates with that of Doumbo et al. (1992) who reported on severe malaria children in a pediatric hospital of Mali. Another study likewise reported a protective effect of SCT against severe forms of malaria in the neighboring country of Burkina Faso [14]. Curiously, our study found that SCT provides significant protection against severe malaria in female but not male children of the villages of Kangaba and Kela (Table I). The reason for this differential signal of protection in the children is not known. Whether it may relate to additional sex-linked genetic factors or particular environmental conditions of the villages is a question that will require further investigation. Table I Distribution of Hemoglobin Types Among Uncomplicated and Severe Cases Malaria in Malian Children In a previous article, we reported that the hemizygous G6PD (A−) condition in the male children of Kangaba and Kela is associated with protection against severe malaria [9]. With this evidence in hand and also with evidence for a high degree of severe protection by SCT in female children, we tested whether an enhanced protective effect might be detected when the G6PD (A−) polymorphism and SCT were present in combination. In hemoglobin AS females heterozygous for G6PD (A−), the occurrence of severe malaria in four individuals suggested no synergistic or additive effect of the two conditions; instead, an OR of 15 (95%CI 2.07–132.31; P = 0.003) suggested the possibility of interference (negative epistasis) between G6PD (A−) heterozygosity and sickle trait in the female children (Table II). However, in sickle trait males with the hemizygous G6PD (A−) condition, no such evidence was found negative epistasis between sickle trait and G6PD (A−) heterozygosity (OR = 0.47; 95CI 0.07–2.40*; P = 0.53). This may reflect no interference due to an absence of a detectable protective activity from SCT in the male children of Kangaba and Kela (discussed above). However, considering the low numbers of severe malaria cases with both sickle trait and a G6PD (A−) condition in our study, additional studies with greater numbers of subjects will be required to further evaluate the possibilities suggested here. Table II Prevalence of G6PD Types in Malian Sickle Trait Children with Uncomplicated or Severe Malaria Our observations invite consideration of the molecular mechanisms by which various erythrocyte polymorphisms protect against severe malaria. A report from Kenya recently provided evidence for negative epistasis between SCT and alpha-thalassemia in protection against malaria [16]. How the protective mechanisms of these and other conditions including G6PD (A−) might interact to mutually interfere in malaria protection remains to be resolved. By the way, more recent study with a limited number of patients has shown that G6PD deficiency and SCT have no effect on the severity of anemia in children infected with both HIV-1 and P. falciparum [17] despite the high proportion of G6PD deficiency in coinfected children. Further study with large sample size is needed to confirm this observation. Understanding the interaction of malaria protective factors in various infectious diseases may be a valuable tool of medical interest. Our evaluation of data was previously collected in the villages of Kangaba and Kela, Mali [9]. Subjects in the case–control study included children 10 years or less of age who presented with clinical symptoms of malaria. Microscopic confirmations of parasitemia, assignments of the cases into uncomplicated or severe malaria, and hemoglobin typing and G6PD (A−) detection were as described [9]. Data evaluation and analysis were performed under consents and protocols approved by Institutional Review Boards of the National Institute of Allergy and Infectious Diseases, Bethesda, MD and of the University of Bamako, Mali.

Although it is true that MIDAS syndrome, Aicardi syndrome and Goltz syndrome show the same transmission, representing X-linked dominant traits with lethality of hemizygote male embryos, and have a number of anomalies such as defects of the eyes or brain in common, it should be noted that MIDAS syndrome and Goltz syndrome have so far never occurred as alternating phenotypes within the same family. In addition, the observation of MIDAS syndrome in a mother and her daughter lends additional support to the notion that this syndrome represents a distinct entity. 3 refs., 4 figs.

When the fibroblast from a patient with Menkes kinky hair disease (MKHD) was cultured in a copper-enriched medium, the rounded, detached and floating cells increased in number. Cell proliferation was also inhibited considerably in the fibroblast from MKHD as compared to that from the normal control. The fibroblast from hemizygote of the macular mouse showed a similar sensitivity for copper in culture medium. Copper content was significantly increased in the cultured fibroblasts from the patient with MKHD and the hemizygote of the macular mouse in a copper-enriched medium compared to that in the fibroblast from the respective control. These results were well identical to those in literatures concerning MKHD and indicate that the fibroblast from the hemizygote of the macular mouse biochemically show a close similarity to those from MKHD and that the macular mouse serves cellbiologically as a model of MKHD.

New radiolabeled oligosaccharides were prepared from various glycosaminogly-cans for the purpose of diagnosis of mucopolysaccharidosis and glycosphingoli-pidosis and of differentiation of enzymatic heterogeneity. Hunter syndrome hemizygote and heterozygote could be successfully diagnosed using hair roots as an enzyme source. The deficiency of galactose-6-sulfate sulfatase was observed in Morquio syndrome in addition to the deficiency of N-acetyl-galactosamine-6-sulfate sulfatase. Tay-Sachs disease was diagnosed without separation of hexosaminidase using hyaluronic acid-derived trisaccharide as sub-strate, Trisaccharide substrate derived from keratan sulfate could be used for the diganosis of GM1-gangliosidosis, however, it was not useful for the dif-ferentiation of type 1 and type 2.