Autosomal-dominant hypotrichosis with woolly hair: Novel gene locus on chromosome 4q35.1-q35.2

Autoři: Annika E. Schlaweck aff001;  Rachid Tazi-Ahnini aff002;  F. Buket Ü. Basmanav aff001;  Javed Mohungoo aff003;  Sandra M. Pasternack-Ziach aff001;  Manuel Mattheisen aff004;  Ana-Maria Oprisoreanu aff005;  Aytaj Humbatova aff001;  Sabrina Wolf aff001;  Andrew Messenger aff003;  Regina C. Betz aff001
Působiště autorů: Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany aff001;  Department of Infection, Immunity, and Cardiovascular Disease, The Medical School, University of Sheffield, Sheffield, United Kingdom aff002;  Department of Dermatology, Royal Hallamshire Hospital, Sheffield, United Kingdom aff003;  Department of Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Würzburg, Würzburg, Germany aff004;  Department of Neuropathology and Department of Epileptology, University Hospital Bonn, Bonn, Germany aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225943


Hypotrichosis simplex (HS) with and without woolly hair (WH) comprises a group of rare, monogenic disorders of hair loss. Patients present with a diffuse loss of scalp and/or body hair, which usually begins in early childhood and progresses into adulthood. Some of the patients also show hair that is tightly curled. Approximately 10 genes for autosomal recessive and autosomal dominant forms of HS have been identified in the last decade, among them five genes for the dominant form. We collected blood and buccal samples from 17 individuals of a large British family with HS and WH. After having sequenced all known dominant genes for HS in this family without the identification of any disease causing mutation, we performed a genome-wide scan, using the HumanLinkage-24 BeadChip, followed by a classical linkage analysis; and whole exome-sequencing (WES). Evidence for linkage was found for a region on chromosome 4q35.1-q35.2 with a maximum LOD score of 3.61. WES led to the identification of a mutation in the gene SORBS2, encoding sorbin and SH3 domain containing 2. Unfortunately, we could not find an additional mutation in any other patient/family with HS; and in cell culture, we could not observe any difference between cloned wildtype and mutant SORBS2 using western blotting and immunofluorescence analyses. Therefore, at present, SORBS2 cannot be considered a definite disease gene for this phenotype. However, the locus on chromosome 4q is a robust and novel finding for hypotrichosis with woolly hair. Further fine mapping and sequencing efforts are therefore warranted in order to confirm SORBS2 as a plausible HS disease gene.

Klíčová slova:

Cytoskeletal proteins – Cytoskeleton – Gene sequencing – Genetic loci – Hair – Immunofluorescence – Linkage analysis – Scalp


1. Shimomura Y. Journey toward unraveling the molecular basis of hereditary hair disorders. J Dermatol Sci. 2016 Dec;84:232–8. doi: 10.1016/j.jdermsci.2016.08.006 27523806

2. Betz RC, Cabral RM, Christiano AM, Sprecher E. Unveiling the roots of monogenic genodermatoses: genotrichoses as a paradigm. J Invest Dermatol. 2012 Mar;132(3 Pt 2):906–14. doi: 10.1038/jid.2011.408 22170492

3. Romano MT, Tafazzoli A, Mattern M, Sivalingam S, Wolf S, Rupp A, et al. Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex. Am J Hum Genet. 2018 Nov 1;103(5):777–85. doi: 10.1016/j.ajhg.2018.09.011 30401459

4. Ü Basmanav FB, Cau L, Tafazzoli A, Mechin MC, Wolf S, Romano MT, et al. Mutations in Three Genes Encoding Proteins Involved in Hair Shaft Formation Cause Uncombable Hair Syndrome. Am J Hum Genet. 2016 Dec 1;99(6):1292–304. doi: 10.1016/j.ajhg.2016.10.004 27866708

5. Rüschendorf F, Nürnberg P. ALOHOMORA: a tool for linkage analysis using 10K SNP array data. Bioinformatics (Oxford, England). 2005 May 1;21(9):2123–5.

6. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics (Oxford, England). 2009 Jul 15;25(14):1754–60.

7. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010 Sep;20(9):1297–303. doi: 10.1101/gr.107524.110 20644199

8. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics (Oxford, England). 2009 Aug 15;25(16):2078–9.

9. Fredriksson-Lidman K, Van Itallie CM, Tietgens AJ, Anderson JM Sorbin and SH3 domain-containing protein 2 (SORBS2) is a component of the acto-myosin ring at the apical junctional complex in epithelial cells. PLoS One 2017 Sep 29;12(9):e0185448. doi: 10.1371/journal.pone.0185448 28961272

10. Wang B, Golemis EA, Kruh GD. ArgBP2, a multiple Src homology 3 domain-containing, Arg/Abl-interacting protein, is phosphorylated in v-Abl-transformed cells and localized in stress fibers and cardiocyte Z-disks. J Biol Chem. 1997 Jul 11;272(28):17542–50. doi: 10.1074/jbc.272.28.17542 9211900

11. Anekal PV, Yong J, Manser E. Arg kinase-binding protein 2 (ArgBP2) interaction with alpha-actinin and actin stress fibers inhibits cell migration. J Biol Chem. 2015 Jan 23;290(4):2112–25. doi: 10.1074/jbc.M114.610725 25429109

12. Cestra G, Toomre D, Chang S, De Camilli P. The Abl/Arg substrate ArgBP2/nArgBP2 coordinates the function of multiple regulatory mechanisms converging on the actin cytoskeleton. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1731–6. doi: 10.1073/pnas.0409376102 15659545

13. Kioka N, Ueda K, Amachi T. Vinexin, CAP/ponsin, ArgBP2: a novel adaptor protein family regulating cytoskeletal organization and signal transduction. Cell Struct Funct. 2002 Feb;27(1):1–7. 11937713

14. Liesenfeld M, Mosig S, Funke H, Jansen L, Runnebaum IB, Durst M, et al. SORBS2 and TLR3 induce premature senescence in primary human fibroblasts and keratinocytes. BMC Cancer. 2013 Oct 29;13:507. doi: 10.1186/1471-2407-13-507 24165198

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