Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex

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• 作者：Sandra M. Pasternack¹ ; Melanie Refke¹ ; Elham Paknia² ; Hans Christian Hennies³ ; ⁴ ; ⁵ ; Thomas Franz⁶ ; Niklas Sch&auml ; fer¹ ; ¹³ ; Alan Fryer⁷ ; Maurice van Steensel⁸ ; ⁹ ; Elizabeth Sweeney⁷ ; Miquel Just¹⁰ ; ¹⁴ ; Clemens Grimm² ; Roland Kruse¹¹ ; Carlos Ferrá ; ndiz¹⁰ ; Markus M. N&ouml ; then¹ ; ¹² ; Utz Fischer² ; Regina C. Betz¹ ; ^{regina.betz@uni-bonn.de}
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：10 January, 2013
• 年：2013
• 卷：92
• 期：1
• 页码：81-87
• 全文大小：759 K

文摘

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 m>SNRPEm> 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. m>SNRPEm> 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 m>SNRPEm> 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.