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

Sandra M Pasternack, Melanie Refke, Elham Paknia, Hans Christian Hennies, Thomas Franz, Niklas Schäfer, Alan Fryer, Maurice van Steensel, Elizabeth Sweeney, Miquel Just, Clemens Grimm, Roland Kruse, Carlos Ferrándiz, Markus M Nöthen, Utz Fischer, Regina C Betz

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)81-87
Number of pages7
JournalAmerican Journal of Human Genetics
Volume92
Issue number1
DOIs
Publication statusPublished - 10 Jan 2013
Externally publishedYes

Fingerprint

Spliceosomes
Alopecia
Mutation
Initiator Codon
Proteins
Tunisia
RNA Precursors
Missense Mutation
Mutant Proteins
Hair
Glycine
Serine
Fluorescent Antibody Technique
Chromosomes
Western Blotting
Phenotype
Hypotrichosis simplex
Growth

Cite this

Pasternack, Sandra M ; Refke, Melanie ; Paknia, Elham ; Hennies, Hans Christian ; Franz, Thomas ; Schäfer, Niklas ; Fryer, Alan ; van Steensel, Maurice ; Sweeney, Elizabeth ; Just, Miquel ; Grimm, Clemens ; Kruse, Roland ; Ferrándiz, Carlos ; Nöthen, Markus M ; Fischer, Utz ; Betz, Regina C. / Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex. In: American Journal of Human Genetics. 2013 ; Vol. 92, No. 1. pp. 81-87.
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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.",
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Pasternack, SM, Refke, M, Paknia, E, Hennies, HC, Franz, T, Schäfer, N, Fryer, A, van Steensel, M, Sweeney, E, Just, M, Grimm, C, Kruse, R, Ferrándiz, C, Nöthen, MM, Fischer, U & Betz, RC 2013, 'Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex', American Journal of Human Genetics, vol. 92, no. 1, pp. 81-87. https://doi.org/10.1016/j.ajhg.2012.10.022

Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex. / Pasternack, Sandra M; Refke, Melanie; Paknia, Elham; Hennies, Hans Christian; Franz, Thomas; Schäfer, Niklas; Fryer, Alan; van Steensel, Maurice; Sweeney, Elizabeth; Just, Miquel; Grimm, Clemens; Kruse, Roland; Ferrándiz, Carlos; Nöthen, Markus M; Fischer, Utz; Betz, Regina C.

In: American Journal of Human Genetics, Vol. 92, No. 1, 10.01.2013, p. 81-87.

Research output: Contribution to journalArticle

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T1 - Mutations in SNRPE, which Encodes a Core Protein of the Spliceosome, Cause Autosomal-Dominant Hypotrichosis Simplex

AU - Pasternack, Sandra M

AU - Refke, Melanie

AU - Paknia, Elham

AU - Hennies, Hans Christian

AU - Franz, Thomas

AU - Schäfer, Niklas

AU - Fryer, Alan

AU - van Steensel, Maurice

AU - Sweeney, Elizabeth

AU - Just, Miquel

AU - Grimm, Clemens

AU - Kruse, Roland

AU - Ferrándiz, Carlos

AU - Nöthen, Markus M

AU - Fischer, Utz

AU - Betz, Regina C

N1 - Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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N2 - 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.

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KW - Female

KW - Genetic Linkage

KW - Humans

KW - Hypotrichosis

KW - Male

KW - Mutation

KW - Pedigree

KW - Spliceosomes

KW - snRNP Core Proteins

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

UR - http://www.cell.com/ajhg/home

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DO - 10.1016/j.ajhg.2012.10.022

M3 - Article

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JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

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