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Archives of Dermatological Research
Published in: Archives of Dermatological Research 9/2015

01-11-2015 | Original Paper

A novel homozygous variant in the dsp gene underlies the first case of non-syndromic form of alopecia

Authors: Abid Jan, Sulman Basit, Salma M. Wakil, Khushnooda Ramzan, Wasim Ahmad

Published in: Archives of Dermatological Research | Issue 9/2015

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Abstract

Autosomal recessive forms of hair loss (alopecia) disorders have previously been associated with variants in at least five different genes including hairless (HR), desmoglein-4 (DSG4), desmocollin-3 (DSC3), lipase-H (LIPH), and lysophosphatidic acid receptor 6 (LPAR6). Here, we report the first familial case of alopecia resulting from a novel homozygous variant in the DSP gene. Since previous reports indicated the presence of heart abnormalities in patients carrying variants in the DSP gene; therefore, the echocardiographic evaluations of all affected members were performed. The results clearly excluded the presence of any form of heart abnormality in patients of the present family. Human genome scan mapped a disease locus on chromosome 6p25.1–p23, harboring DSP gene. Sequence analysis identified a novel homozygous missense variant [c.1493C > T (p.Pro498Leu)] in the DSP gene as the underlying genetic cause of non-syndromic alopecia in the family. The transition alters the completely conserved Pro498 residue in the SH3 domain of plakin that contributes to the stability and rigidity of this subfamily of spectrin repeats (SRs) containing proteins. Our study strengthens the evidence that hereditary hair loss disorders are genetically heterogeneous and imply that isolated form of alopecia is allelic with cardiocutaneous syndromes.
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Literature
1.
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249PubMedCentralCrossRefPubMed
2.
Ahmad W, Faiyaz ul Haque M, Brancolini V, Tsou HC, ul Haque S, Lam H, Aita VM, Owen J, deBlaquiere M, Frank J, Cserhalmi-Friedman PB, Leask A, McGrath JA, Peacocke M, Ahmad M, Ott J, Christiano AM (1998) Alopecia universalis associated with a mutation in the human hairless gene. Science 279:720–724CrossRefPubMed
3.
Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (2003) A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair. J Am Coll Cardiol 42:319–327CrossRefPubMed
4.
Ali G, Chishti MS, Raza SI, John P, Ahmad W (2007) A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis. Hum Genet 121:319–325CrossRefPubMed
5.
Angst BD, Nilles LA, Green KJ (1990) Desmoplakin II expression is not restricted to stratified epithelia. J Cell Sci 97(Pt 2):247–257PubMed
6.
Ayub M, Basit S, Jelani M, Ur Rehman F, Iqbal M, Yasinzai M, Ahmad W (2009) A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. Am J Hum Genet 85:515–520PubMedCentralCrossRefPubMed
7.
Azeem Z, Jelani M, Naz G, Tariq M, Wasif N, Kamran-Ul-Hassan Naqvi S, Ayub M, Yasinzai M, Amin-Ud-Din M, Wali A, Ali G, Chishti MS, Ahmad W (2008) Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3). Hum Genet 123:515–519CrossRefPubMed
8.
Basit S, Ali G, Wasif N, Ansar M, Ahmad W (2010) Genetic mapping of a novel hypotrichosis locus to chromosome 7p21.3-p22.3 in a Pakistani family and screening of the candidate genes. Hum Genet 128:213–220CrossRefPubMed
9.
10.
Carvajal-Huerta L (1998) Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy. J Am Acad Dermatol 39:418–421CrossRefPubMed
11.
Cichon S, Anker M, Vogt IR, Rohleder H, Putzstuck M, Hillmer A, Farooq SA, Al-Dhafri KS, Ahmad M, Haque S, Rietschel M, Propping P, Kruse R, Nothen MM (1998) Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum Mol Genet 7:1671–1679CrossRefPubMed
12.
13.
Djinovic-Carugo K, Young P, Gautel M, Saraste M (1999) Structure of the alpha-actinin rod: molecular basis for cross-linking of actin filaments. Cell 98:537–546CrossRefPubMed
14.
15.
Green KJ, Kowalczyk AP, Bornslaeger EA, Palka HL, Norvell SM (1998) Desmosomes: integrators of mechanical integrity in tissues. Biol Bull 194:374-376; discussion 376-377
16.
Grum VL, Li D, MacDonald RI, Mondragon A (1999) Structures of two repeats of spectrin suggest models of flexibility. Cell 98:523–535CrossRefPubMed
17.
Headon DJ, Overbeek PA (1999) Involvement of a novel Tnf receptor homologue in hair follicle induction. Nat Genet 22:370–374CrossRefPubMed
18.
Hoffmann K, Lindner TH (2005) easyLINKAGE-Plus - automated linkage analyses using large-scale SNP data. Bioinformatics 21:3565–3567CrossRefPubMed
19.
Jefferson JJ, Ciatto C, Shapiro L, Liem RK (2007) Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily. J Mol Biol 366:244–257PubMedCentralCrossRefPubMed
20.
John P, Ali G, Chishti MS, Naqvi SM, Leal SM, Ahmad W (2006) Localization of a novel locus for alopecia with mental retardation syndrome to chromosome 3q26.33-q27.3. Hum Genet 118:665–667CrossRefPubMed
21.
Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A, Pas HH (2005) Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Am J Hum Genet 77:653–660PubMedCentralCrossRefPubMed
22.
Kazantseva A, Goltsov A, Zinchenko R, Grigorenko AP, Abrukova AV, Moliaka YK, Kirillov AG, Guo Z, Lyle S, Ginter EK, Rogaev EI (2006) Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH. Science 314:982–985CrossRefPubMed
23.
Khan B, Basit S, Touseef M, Tariq M, Khan MN, Ahmad W (2012) A novel chondroectodermal dysplasia mapped to chromosome 2q24.1-q31.1. Eur J Med Genet 55:455–460CrossRefPubMed
24.
Kjaer KW, Hansen L, Schwabe GC, Marques-de-Faria AP, Eiberg H, Mundlos S, Tommerup N, Rosenberg T (2005) Distinct CDH3 mutations cause ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). J Med Genet 42:292–298PubMedCentralCrossRefPubMed
25.
Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaughnessy R, Mahoney MG, Levy M, Montagutelli X, Ahmad W, Aita VM, Gordon D, Uitto J, Whiting D, Ott J, Fischer S, Gilliam TC, Jahoda CA, Morris RJ, Panteleyev AA, Nguyen VT, Christiano AM (2003) Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113:249–260CrossRefPubMed
26.
Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM, Denning MF, Green KJ (1997) The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes. J Cell Biol 139:773–784PubMedCentralCrossRefPubMed
27.
Lai Cheong JE, Wessagowit V, McGrath JA (2005) Molecular abnormalities of the desmosomal protein desmoplakin in human disease. Clin Exp Dermatol 30:261–266CrossRefPubMed
28.
Leung CL, Green KJ, Liem RK (2002) Plakins: a family of versatile cytolinker proteins. Trends Cell Biol 12:37–45CrossRefPubMed
29.
Mahoney MG, Sadowski S, Brennan D, Pikander P, Saukko P, Wahl J, Aho H, Heikinheimo K, Bruckner-Tuderman L, Fertala A, Peltonen J, Uitto J, Peltonen S (2010) Compound heterozygous desmoplakin mutations result in a phenotype with a combination of myocardial, skin, hair, and enamel abnormalities. J Invest Dermatol 130:968–978PubMedCentralCrossRefPubMed
30.
Mehmood S, Jan A, Muhammad D, Ahmad F, Mir H, Younus M, Ali G, Ayub M, Ansar M, Ahmad W (2014) Mutations in the lipase-H gene causing autosomal recessive hypotrichosis and woolly hair. Australas J Dermatol
31.
Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J (1999) Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet 22:366–369CrossRefPubMed
32.
North AJ, Bardsley WG, Hyam J, Bornslaeger EA, Cordingley HC, Trinnaman B, Hatzfeld M, Green KJ, Magee AI, Garrod DR (1999) Molecular map of the desmosomal plaque. J Cell Sci 112(Pt 23):4325–4336PubMed
33.
Ortega E, Buey RM, Sonnenberg A, de Pereda JM (2011) The structure of the plakin domain of plectin reveals a non-canonical SH3 domain interacting with its fourth spectrin repeat. J Biol Chem 286:12429–12438PubMedCentralCrossRefPubMed
34.
Pasternack SM, von Kugelgen I, Al Aboud K, Lee YA, Ruschendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, Nurnberg P, Nothen MM, Betz RC (2008) G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 40:329–334CrossRefPubMed
35.
36.
Raza SI, Muhammad D, Jan A, Ali RH, Hassan M, Ahmad W, Rashid S (2014) In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis. PLoS ONE 9:e104756PubMedCentralCrossRefPubMed
37.
Seelow D, Schuelke M (2012) HomozygosityMapper2012 - bridging the gap between homozygosity mapping and deep sequencing. Nucleic Acids Res 40:W516–W520PubMedCentralCrossRefPubMed
38.
39.
Shimomura Y, Wajid M, Ishii Y, Shapiro L, Petukhova L, Gordon D, Christiano AM (2008) Disruption of P2RY5, an orphan G protein-coupled receptor, underlies autosomal recessive woolly hair. Nat Genet 40:335–339CrossRefPubMed
40.
Sprecher E, Bergman R, Richard G, Lurie R, Shalev S, Petronius D, Shalata A, Anbinder Y, Leibu R, Perlman I, Cohen N, Szargel R (2001) Hypotrichosis with juvenile macular dystrophy is caused by a mutation in CDH3, encoding P-cadherin. Nat Genet 29:134–136CrossRefPubMed
41.
Tanaka A, Lai-Cheong JE, Cafe ME, Gontijo B, Salomao PR, Pereira L, McGrath JA (2009) Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families. Br J Dermatol 160:692–697CrossRefPubMed
42.
Tariq M, Ayub M, Jelani M, Basit S, Naz G, Wasif N, Raza SI, Naveed AK, ullah Khan S, Azeem Z, Yasinzai M, Wali A, Ali G, Chishti MS, Ahmad W (2009) Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families. Br J Dermatol 160:1006–1010CrossRefPubMed
43.
Ullah A, Raza SI, Ali RH, Naveed AK, Jan A, Rizvi SD, Satti R, Ahmad W (2015) A novel deletion mutation in the DSG4 gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families. Clin Exp Dermatol 40:78–84CrossRefPubMed
44.
Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, Rozen SG (2012) Primer3 - new capabilities and interfaces. Nucleic Acids Res 40:e115PubMedCentralCrossRefPubMed
45.
Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserili H, Sahin SE, Dupont E, Severs NJ, Leigh IM, Yuksel-Apak M, Kelsell DP, Wollnik B (2006) Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome. J Med Genet 43:e5PubMedCentralCrossRefPubMed
46.
Wali A, Ali G, John P, Lee K, Chishti MS, Leal SM, Ahmad W (2007) Mapping of a gene for alopecia with mental retardation syndrome (APMR3) on chromosome 18q11.2-q12.2. Ann Hum Genet 71:570–577CrossRefPubMed
47.
Wali A, John P, Gul A, Lee K, Chishti MS, Ali G, Hassan MJ, Leal SM, Ahmad W (2006) A novel locus for alopecia with mental retardation syndrome (APMR2) maps to chromosome 3q26.2-q26.31. Clin Genet 70:233–239CrossRefPubMed
48.
Whittock NV, Ashton GH, Dopping-Hepenstal PJ, Gratian MJ, Keane FM, Eady RA, McGrath JA (1999) Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. J Invest Dermatol 113:940–946CrossRefPubMed
49.
World Medical A (2013) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 310:2191–2194CrossRef
50.
Yan Y, Winograd E, Viel A, Cronin T, Harrison SC, Branton D (1993) Crystal structure of the repetitive segments of spectrin. Science 262:2027–2030CrossRefPubMed
Metadata
Title
A novel homozygous variant in the dsp gene underlies the first case of non-syndromic form of alopecia
Authors
Abid Jan
Sulman Basit
Salma M. Wakil
Khushnooda Ramzan
Wasim Ahmad
Publication date
01-11-2015
Publisher
Springer Berlin Heidelberg
Published in
Archives of Dermatological Research / Issue 9/2015
Print ISSN: 0340-3696
Electronic ISSN: 1432-069X
DOI
https://doi.org/10.1007/s00403-015-1590-y

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