title: Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Pasternack
authors.forename: Melanie
authors.initials: M
authors.lastname: Refke
authors.forename: Elham
authors.initials: E
authors.lastname: Paknia
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: Thomas
authors.initials: T
authors.lastname: Franz
authors.forename: Niklas
authors.initials: N
authors.lastname: Schäfer
authors.forename: Alan
authors.initials: A
authors.lastname: Fryer
authors.forename: Maurice
authors.initials: M
authors.lastname: van Steensel
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sweeney
authors.forename: Miquel
authors.initials: M
authors.lastname: Just
authors.forename: Clemens
authors.initials: C
authors.lastname: Grimm
authors.forename: Roland
authors.initials: R
authors.lastname: Kruse
authors.forename: Carlos
authors.initials: C
authors.lastname: Ferrándiz
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Utz
authors.initials: U
authors.lastname: Fischer
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
mesh_terms: D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D017381:Spliceosomes / Q000235:genetics; D055517:snRNP Core Proteins / Q000235:genetics*
chemical_list: C526413:SNRPE protein, human; D055517:snRNP Core Proteins