Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex.

Hypotrichosis simplex (HS) comprises a group of hereditary isolated alopecias that are characterized by a diffuse and progressive loss of hair starting in childhood and shows a wide phenotypic variability. We mapped an autosomal-dominant form of HS to chromosome 1q31.3-1q41 in a Spanish family. By direct sequencing, we identified the heterozygous mutation c.1A>G (p.Met1?) in SNRPE that results in loss of the start codon of the transcript. We identified the same mutation in a simplex HS case from the UK and an additional mutation (c.133G>A [p.Gly45Ser]) in a simplex HS case originating from Tunisia. SNRPE encodes a core protein of U snRNPs, the key factors of the pre-mRNA processing spliceosome. The missense mutation c.133G>A leads to a glycine to serine substitution and is predicted to disrupt the structure of SNRPE. Western blot analyses of HEK293T cells expressing SNRPE c.1A>G revealed an N-terminally truncated protein, and therefore the mutation might result in use of an alternative in-frame downstream start codon. Subcellular localization of mutant SNRPE by immunofluorescence analyses as well as incorporation of mutant SNRPE proteins into U snRNPs was found to be normal, suggesting that the function of U snRNPs in splicing, rather than their biogenesis, is affected. In this report we link a core component of the spliceosome to hair loss, thus adding another specific factor in the complexity of hair growth. Furthermore, our findings extend the range of human phenotypes that are linked to the splicing machinery.

Selected variants of the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2 and the sex steroid hormone receptors ESR1, ESR2 and PGR: no association with female pattern hair loss identified.

Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.

Marie Unna hereditary hypotrichosis: identification of a U2HR mutation in the family from the original 1925 report.

BACKGROUND: In 1925, Dr Marie Unna described a rare form of hereditary hypotrichosis in a German multigenerational family. This was later termed "Marie Unna hereditary hypotrichosis" (MUHH). MUHH is an autosomal dominant disorder that is characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty. Causal mutations in U2HR, an inhibitory upstream open reading frame in the 5'-untranslated region of the human hairless (HR) gene, were recently identified in several unrelated MUHH families from various ethnic backgrounds. OBJECTIVE: Although there have been several clinical reports of descendants of the originally described family, the molecular cause of disease in this particular family has not been established. The aim of this study was to investigate descendants of this family and to analyze their DNA for the presence of U2HR mutations. METHODS: Descendants of the family (including one affected individual) were examined clinically. Direct sequencing of U2HR was performed. Enzymatic digestion using the restriction enzyme NcoI was performed to confirm the sequencing results. RESULTS: The index patient displayed the typical MUHH pattern of hair loss and was found to carry the disease-causing c.3G>A (p.M1I) U2HR mutation. This mutation was not detected in unaffected family members. LIMITATIONS: Only one affected family member was investigated. CONCLUSIONS: Eighty-five years after the first description of this rare form of alopecia, the disease-causing mutation in the originally reported family has been identified.

Follow-up study of the first genome-wide association scan in alopecia areata: IL13 and KIAA0350 as susceptibility loci supported with genome-wide significance.

Recently, the first genome-wide association study (GWAS) of alopecia areata (AA) was conducted in a North-American sample, and this identified eight susceptibility loci surpassing genome-wide significance. The aim of the present follow-up association analysis was to confirm five of these eight loci (single-nucleotide polymorphisms (SNPs) from the CTLA4, IL-2RA, and HLA regions were not included due to previous own findings) and test 12 other loci from the GWAS, which did not surpass the threshold for genome-wide significance. Twenty-three SNPs from the 17 loci were investigated using a sample of 1,702 Central European AA patients and 1,723 controls. Of the five loci with previously reported genome-wide significance, association was confirmed for all of these: ULBP3/ULBP6, PRDX5, IL-2/IL-21, STX17, and IKZF4/ERBB3 (P-value <0.05). To detect robust evidence for association among the 12 other loci, a meta-analysis of the present association data and the data of the recent GWAS was performed. Genome-wide significant association was found for rs20541 (P(comb)=7.52 × 10(-10); odds ratio (OR)=1.30 (1.23-1.38)) and rs998592 (P(comb)=1.11 × 10(-11); OR=1.28 (1.21-1.36)), thus establishing IL-13 and KIAA0350/CLEC16A as susceptibility loci for AA. Interestingly, IL-13 and KIAA0350/CLEC16A are susceptibility loci for other autoimmune diseases, supporting the hypothesis of shared pathways of autoimmune susceptibility.

Tyrosinemia type II (Richner-Hanhart syndrome): a new mutation in the TAT gene.

In the present study we report the clinical features and the molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in a young girl from Croatia with Richner-Hanhart syndrome, mainly suffering from photophobia, hyperkeratosis of the palmes and soles and slight neurological abnormalities. Sequencing analysis of the TAT gene revealed a novel homozygous missense mutation c.1250G>A (p.R417Q) in exon 12, and herewith confirmed the clinical diagnosis. Showing the first symptoms in babyhood, at the age of 8 years it was for the first time clinically diagnosed that the patient suffers from tyrosinemia type II and a therapy with tyrosine and phenylalanine reduced diet has been started successfully. All symptoms disappeared within 2-4 weeks. Since that time, we have been following the girl until today for more than ten years. She is in a good condition, and attends the normal high school program.

Efficacy of ablative laser treatment in Galli-Galli disease.

BACKGROUND: Galli-Galli disease (GGD) represents a rare genodermatosis that is clinically characterized by progressive reticulate hyperpigmentation of the flexures accompanied by itching and pain. To date, no convincing treatment options are known for GGD. We sought to examine the therapeutic potential of ablative laser treatment in a patient with genetically confirmed GGD. OBSERVATIONS: We describe a 68-year-old man with refractory bilateral axillary GGD accompanied by severe itching and pain. His clinical picture and histologic findings were consistent with GGD. Direct sequencing analysis of the KRT5 gene identified the causative mutation, c.418dupA, and confirmed the clinical diagnosis. The patient was treated with the erbium:YAG laser in 2 consecutive sessions for each side and was followed up for 12 months. Ablative laser treatment led to complete resolution of clinical symptoms and a good clinical result with only minimal scarring and dyspigmentation. CONCLUSIONS: This article demonstrates the efficacy of ablative laser treatment in a patient with genetically confirmed refractory GGD. However, further studies with longer follow-up are required to confirm these results.