Hairless Gene Nonsense Mutations in Alopecia Universalis: A Case Report.
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ABSTRACT:
SUBMITTER: Heidary H
PROVIDER: S-EPMC8410955 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC10108610 | biostudies-literature
Project description:Atrichia with papular lesions (APL) is a rare autosomal recessive form of inherited alopecia. Affected individuals present with a distinct pattern of total hair loss on the scalp, axilla and body shortly after birth and are essentially devoid of eyelashes and eyebrows. This form of hair loss is irreversible and the histology is consistent with an absence of mature hair follicles. In addition to total atrichia, APL patients also present with papules and follicular cysts filled with cornified material. Mutations in the Hairless (HR) gene have been shown to underlie APL.Here, we studied five unrelated large Pakistani families with clinical manifestations of APL.Based on previous reports of HR mutations in APL, we performed direct DNA sequencing analysis.DNA sequencing of the HR gene in APL patients revealed three novel nonsense mutations in five unrelated families. All affected individuals were homozygous for a nonsense mutation due to C-to-T transitions at different positions in the amino acid sequence. Two families carry the mutation Q323X (CAG-TAG) in exon 3, two families harbor the mutation Q502X (CAG-TAG) in exon 6, and one family had a mutation at R940X (CGA-TGA) in exon 14. Haplotype analysis revealed that all affected individuals of both APL1 and APL16 families were homozygous for the same haplotype, and likewise, the mutation in families APL2 and APL19 was on the same haplotype.We report three novel nonsense mutations in the HR gene in APL. Two of the newly identified mutations, Q323X and Q502X, were found to be shared between unrelated families and marker analysis confirmed an identical homozygous haplotype for APL1 and APL16, and for APL2 and APL19. These findings suggest that Q323X and Q502X did not arise independently, but instead appear to have been propagated in the population. Collectively, these findings contribute further evidence for the involvement of hairless mutations in papular atrichia.
| S-EPMC3341169 | biostudies-literature
Project description:Alopecia areata is among the most prevalent autoimmune diseases, yet compared with other autoimmune conditions, it is not well studied. This in part results from limitations in the C3H/HeJ mouse and DEBR rat model systems most commonly used to study the disease, which display a low frequency and late onset. We describe a novel high-incidence model for spontaneous alopecia areata. The 1MOG244 T cell expresses dual TCRA chains, one of which, when combined with the single TCRB present, promotes the development of CD8(+) T cells with specificity for hair follicles. Retroviral transgenic mice expressing this TCR develop spontaneous alopecia areata at nearly 100% incidence. Disease initially follows a reticular pattern, with regionally cyclic episodes of hair loss and regrowth, and ultimately progresses to alopecia universalis. Alopecia development is associated with CD8(+) T cell activation, migration into the intrafollicular region, and hair follicle destruction. The disease may be adoptively transferred with T lymphocytes and is class I and not class II MHC-dependent. Pathologic T cells primarily express IFNG and IL-17 early in disease, with dramatic increases in cytokine production and recruitment of IL-4 and IL-10 production with disease progression. Inhibition of individual cytokines did not significantly alter disease incidence, potentially indicating redundancy in cytokine responses. These results therefore characterize a new high-incidence model for alopecia areata in C57BL/6J mice, the first to our knowledge to apply a monoclonal TCR, and indicate that class I MHC-restricted CD8(+) T lymphocytes can independently mediate the pathologic response.
| S-EPMC3244525 | biostudies-literature
Project description:ImportanceAlopecia areata (AA) is characterized by nonscarring hair loss of the scalp, face, and/or body. Alopecia totalis (AT) and alopecia universalis (AU) involve complete loss of the scalp and body hair, respectively. The epidemiology of AA in the US remains unclear, having previously been extrapolated from older studies that were limited to specific geographic areas or clinical settings, or from self-reported data.ObjectiveTo estimate the annual prevalence and incidence of AA and AT and/or AU (AT/AU) in the US.Design, setting, and participantsThis retrospective, population-based cohort study was conducted from January 2016 to December 2019 and included enrollees in the IBM MarketScan Commercial Claims and Encounters and Medicare Supplemental databases and their dependents, with plan enrollment during each study calendar year and the year prior.ExposuresPrevalent cases were identified by 1 or more claims for AA or AT/AU (International Statistical Classification of Diseases, Tenth Revision, Clinical Modification [ICD-10-CM] codes L63.x, L63.0, L63.1) during each year of interest or the year prior. Incident cases were identified by 1 or more claims for AA or AT/AU during a specific year and no diagnosis the year prior.Main outcomes and measuresAnnual incidence and prevalence rates were calculated and stratified by age, sex, and region. National employer-sponsored insurance population estimates were obtained using population-based weights.ResultsAmong eligible patients (2016: n = 18 368 [mean (SD) age, 40.6 (17.9) years; 12 295 women (66.9%)]; 2017: n = 14 372 [mean (SD) age, 39.6 (17.7) years; 9195 women (64.0%)]; 2018: n = 14 231 [mean (SD) age, 38.9 (17.3) years; 8998 women (63.2%)]; 2019: n = 13 455 [mean (SD) age, 39.1 (17.4) years; 8322 women (61.9%)]), AA prevalence increased from 0.199% (95% CI, 0.198%-0.200%) in 2016 to 0.222% (95% CI, 0.221%-0.223%) in 2019. Roughly 5% to 10% of prevalent and incident cases of AA were AT/AU. The prevalence of AT/AU increased from 0.012% (95% CI, 0.012%-0.013%) to 0.019% (95% CI, 0.018%-0.019%) from 2016 to 2019. Incidence of AA per 100 000 person-years ranged from 87.39 (95% CI, 86.84-87.96) in 2017 to 92.90 (95% CI, 92.35-93.45) in 2019. Incidence of AT/AU ranged from 7.09 (95% CI, 6.94-7.25) in 2017 to 8.92 (95% CI, 8.75-9.09) in 2016. Prevalence and incidence of AA and AT/AU were higher among female vs male individuals, adults vs children and adolescents, and in the Northeast vs other regions.Conclusions and relevanceThe results of this cohort study suggest that these recent AA prevalence and incidence estimates could help improve current understanding of the disease burden. Further research is warranted to elucidate subpopulation differences and trends in AA in the broader US population.
| S-EPMC9979012 | biostudies-literature
Project description:Congenital alopecia universalis is one of the rarest anomaly which involves skin and appendages. The inheritance pattern can be autosomal recessive, X-linked recessive, or autosomal dominant. However, the most common is autosomal recessive form and it is the most severe phenotype. Twenty-nail dystrophy refers to the condition in which all the twenty nails are affected in the form of excessive ridging and nail plate roughness leading to unsightly lustureless nails. We report a rare case of two siblings with alopecia universalis congenita with twenty-nail dystrophy. To the best of our knowledge, this case is the first case to be reported with such association in both siblings. This case reports highlights the fact that alopecia areata is an autoimmune disease with a genetic predisposition as in our case both siblings had alopecia universalis and nail dystrophy. There was no evidence of any other ectodermal dyplasia and had normal teeth and seat glands. The skin biopsy ruled out congenital atrichia and was suggestive of alopecia areata.
| S-EPMC5551308 | biostudies-other
Project description:BACKGROUND:Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disease, characterized mainly by skin blistering at birth or shortly thereafter, progressive muscle weakness, and rarely by alopecia. EBS-MD is caused by mutations in the PLEC gene (OMIM *601282), which encodes plectin, a structural protein expressed in several tissues, including epithelia and muscle. We describe a patient affected with EBS-MD and diffuse alopecia in which we identified a novel pathogenic mutation by PCR amplification of all coding exons and exon-intron boundaries of PLEC gene, followed by bidirectional Sanger sequencing. CASE PRESENTATION:The patient, a 28-year-old female and only child of consanguineous healthy parents, was born after uneventful pregnancy. At 2 days of age, she developed skin and oral mucosal blistering, accompanied by voice hoarseness. On physical examination as an adult, we observed diffuse non-scarring alopecia on the scalp, onychodystrophy (pachyonychia) in all 20 nails, dental decay, mild dysphonia, and severe muscle atrophy mainly affecting the extremities. Neurological examination showed profoundly diminished reflexes. Mutation analysis revealed the patient to be homozygous for the novel PLEC nonsense mutation - c.7159G?>?T (p.Glu2387*) - located in exon 31. Thismutation predicts the lack of expression of the full-length plectin isoform. CONCLUSION:The present case appears to be the second association of EBS-MD with diffuse alopecia, both cases having different mutations involving PLEC exon 31. It remains to be elucidated whether diffuse alopecia results from PLEC mutations and/or from environmental factors.
| S-EPMC5775598 | biostudies-literature
Project description:Alopecia areata (AA) is a common autoimmune disorder mostly presented as round patches of hair loss and subclassified into alopecia totalis/alopecia universalis (AT/AU) based on the area of alopecia. Although AA is relatively common, only 5% of AA patients progress to AT/AU, which affect the whole scalp and whole body respectively. To determine genetic determinants of this orphan disease, we undertook whole-exome sequencing of 6 samples from AU patients, and 26 variants in immune-related genes were selected as candidates. When an additional 14 AU samples were genotyped for these candidates, 6 of them remained at the level of significance in comparison with 155 Asian controls (p<1.92×10(-3)). Linkage disequilibrium was observed between some of the most significant SNPs, including rs41559420 of HLA-DRB5 (p<0.001, OR 44.57) and rs28362679 of BTNL2 (p<0.001, OR 30.21). While BTNL2 was reported as a general susceptibility gene of AA previously, HLA-DRB5 has not been implicated in AA. In addition, we found several genetic variants in novel genes (HLA-DMB, TLR1, and PMS2) and discovered an additional locus on HLA-A, a known susceptibility gene of AA. This study provides further evidence for the association of previously reported genes with AA and novel findings such as HLA-DRB5, which might represent a hidden culprit gene for AU.
| S-EPMC3543254 | biostudies-literature
Project description:Aspergillary rhinopharyngitis in an equine patient
| PRJEB46193 | ENA
Project description:Autosomal dominant hypocalcemia (ADH1) is a genetic disorder characterized by low serum calcium and low or inappropriately normal levels of parathyroid hormone. The disease is caused by a heterozygous activating mutation of the calcium-sensing receptor (CaSR) gene, encoding a G-Protein-coupled cell membrane sensor of extracellular calcium concentration mainly expressed by parathyroid glands, renal tubules, and the brain. ADH1 has been linked to 113 unique germline mutations, of which nearly 96% are missense mutations. There is often a lack of a clear genotype/phenotype correlation in the reported literature. Here, we described a case series of 6 unrelated ADH1 probands, each one bearing a gain-of-function CaSR mutation, and two children of one of these cases, matching our identified mutations to the same ones previously reported in the literature, and comparing the clinical and biochemical characteristics, as well as the complication profile. As a result of these genetic and clinical comparisons, we propose that a genotype/phenotype correlation may exist because our cases showed similar presentation, characteristics, and severity, with respect to published cases with the same or similar mutations. We also contend that the severity of the presentation is highly influenced by the specific CaSR variant. These findings, however, require further evaluation and assessment with a systematic review.
| S-EPMC10466028 | biostudies-literature
Project description:Microcephaly is a fairly common feature observed in children with delayed development, defined as head circumference less than 2 standard deviations below the mean for age and gender. It may be the result of an acquired insult to the brain, such prenatal or perinatal brain injury (congenital infection or hypoxic ischemic encephalopathy), or be a part of a genetic syndrome. There are over 1000 conditions listed in OMIM (Online Mendelian Inheritance in Man) where microcephaly is a key finding; many of these are associated with specific somatic features and non-CNS anomalies. The term primary microcephaly is used when microcephaly and delayed development are the primary features, and they are not part of another recognized syndrome. In this case report, we present the clinical features of siblings (brother and sister) with primary microcephaly and delayed development, and subtle dysmorphic features. Both children had brain MRI studies that showed periventricular and subcortical T2/FLAIR hyperintensities, without signs of white matter volume loss, and no parenchymal calcifications by CT scan. The family was enrolled in a research study for whole exome sequencing of probands and parents. Analysis of variants determined that the children were compound heterozygotes for nonsense mutations, c.277C>T (p.Arg93*) and c.397C>T (p.Arg133*), in the TRMT10A gene. Mutations in this gene have only recently been reported in children with microcephaly and early onset diabetes mellitus. Our report adds to current knowledge of TRMT10A related neurodevelopmental disorders and demonstrates imaging findings suggestive of delayed or abnormal myelination of the white matter in this disorder. Accurate diagnosis through genomic testing, as in the children described here, allows for early detection and management of medical complications, such as diabetes mellitus.
| S-EPMC4617320 | biostudies-literature