Abstract
Hereditary hypotrichosis is a heterogeneous group of inherited hair loss disorders characterized by diffused or localized thinning or absence of hair affecting scalp, eyebrows and eyelashes, and other body parts. Over the past few years, at least four autosomal dominant and six autosomal recessive forms of hypotrichosis have been described. All these ten forms of hypotrichosis have been mapped on different human chromosomes and the corresponding genes have been identified in most of these cases. In the present study, we have described a six-generation Pakistani consanguineous family with an autosomal recessive transmission of hereditary hypotrichosis. All the five affected individuals of the family showed complete absence of scalp hair and sparse eyebrows and eyelashes. They were born with complete absence of scalp hairs. Facial hair of beard and mustaches were present in all the affected adult male individuals. Papules were observed only on scalp of the affected individuals. A scalp biopsy from an affected individual showed markedly reduced number of hair follicles. Human genome scan using polymorphic microsatellite markers mapped the disease locus on chromosome 7p21.3–p22.3, flanked by markers D7S1532 and D7S3047. A maximum two-point LOD score of 4.74 (θ = 0.00) was obtained at marker D7S481. The linkage interval spans 15.69 cM, which corresponds to 6.59 Mb according to the sequence-based physical map (Build 36.2). Mutation analysis of five potential candidate genes (GNA12, FOXK1, DAGLB, ZNF12, ACTB), located in the linkage interval, did not reveal any functional sequence variant.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97–101
Ahmad W, Faiyaz ul Haque M, Brancolin V, Tsou HC, ul Haque S, Lam H, Aita VM, Owen J, de Blaquiere 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 279:720–724
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 121:319–325
Aslam M, Chahrour MH, Razzaq A, Haque S, Yan K, Leal SM, Ahmad W (2004) A novel locus for autosomal recessive form of hypotrichosis maps to chromosome 3q26.33–q27.3. J Med Genet 41:849–852
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 85:515–520
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 123:515–519
Basit S, Naqvi SK, Wasif N, Ali G, Ansar M, Ahmad W (2008) A novel insertion mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene underlies Grebe-type chondrodysplasia in a consanguineous Pakistani family. BMC Med Genet 9:102
Baumer A, Belli S, Trüeb RM, Schinzel A (2000) An autosomal dominant form of hereditary hypotrichosis simplex maps to 18p11.32–p11.23 in an Italian family. Eur J Hum Genet 8:443–448
Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Hobbs C, Di Marzo V, Doherty P (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468
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 7:1671–1679
Düzenli S, Redler S, Müller M, Polat M, Dogruer D, Pasternack SM, Betz RC (2009) Identification of a U2HR gene mutation in Turkish families with Marie Unna hereditary hypotrichosis. Clin Exp Dermatol 34:953–956
Frank J, Pignata C, Panteleyev AA, Prowse DM, Baden H, Weiner L, Gaetaniello L, Ahmad W, Pozzi N, Cserhalmi-Friedman PB, Aita VM, Uyttendaele H, Gordon D, Ott J, Brissette JL, Christiano AM (1999) Exposing the human nude phenotype. Nature 398:473–474
Gieni RS, Hendzel MJ (2009) Actin dynamics and functions in the interphase nucleus: moving toward an understanding of nuclear polymeric actin. Biochem Cell Biol 87:283–306
Headon DJ, Overbeek PA (1999) Involvement of a novel Tnf receptor homologue in hair follicle induction. Nat Genet 22:370–374
Horev L, Tosti A, Rosen I, Hershko K, Vincenzi C, Nanova K, Mali A, Potikha T, Zlotogorski A (2009) Mutations in lipase H cause autosomal recessive hypotrichosis simplex with woolly hair. Am Acad Dermatol 61:813–818
Jelani M, Wasif N, Ali G, Chishti MS, Ahmad W (2008) A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2). Clin Genet 74:184–188
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 118:665–667
Kalsoom UE, Habib R, Khan B, Ali G, Ali N, Ansar M, Ahmad W (2010) Mutations in lipase H gene underlie autosomal recessive hypotrichosis in five Pakistani families. Acta Derm Venereol 90:93–94
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 314:982–985
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 113:249–260
Levy-NissenbauM E, Betz RC, Frydman M, Simon M, Lahat H, Bakhan T, Goldman B, Bygum A, Pierick M, Hillmer AM, Jonca N, Toribio J, Kruse R, Dewald G, Cichon S, Kubisch C, Guerrin M, Serre G, Nothen NN, Pras E (2003) Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 34:151–153
Luo KT, Yuan J, Shan YX, Li J, Xu M, Cui YH, Tang WW, Wan B, Zhang NL, Wu YM, Yu L (2006) Activation of transcriptional activities of AP1 and SRE by a novel zinc finger protein ZNF445. Gene 367:89–100
Matise TC, Chen F, Chen W, De La Vega FM, Hansen M, He C, Hyland FC, Kennedy GC, Kong X, Murray SS, Ziegle JS, Stewart WC, Buyske S (2007) A second-generation combined linkage physical map of the human genome. Genome Res 17:1783–1786
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 22:366–369
Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65
Naz G, Khan B, Ali G, Azeem Z, Wali A, Ansar M, Ahmad W (2009) Novel missense mutations in lipase H (LIPH) gene causing autosomal recessive hypotrichosis (LAH2). J Dermatol Sci 54:12–16
Naz G, Ali G, Kamran-Ul-Hassan Naqvi S, Azeem Z, Ahmad W (2010) Mapping of a novel autosomal recessive hypotrichosis locus on chromosome 10q11.23–22.3. Hum Genet 127:395–401
Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–107
Nothen MM, Cichon S, Vogt IR, Hemmer S, Kruse R, Knapp M, Holler T, Faiyaz ul Haque M, Haque S, Propping P, Ahmad M, Rietschel M (1998) A gene for universal congenital alopecia maps to chromosome 8p21–22. Am J Hum Genet 62:386–390
O’Connell JR, Weeks DE (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 63:259–266
Pasternack SM, von Kugelgen I, Aboud KA, 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 40:329–334
Rafiq MA, Ansar M, Mahmood S, Haque S, Faiyaz-ul-Haque M, Leal SM, Ahmad W (2004) A recurrent intragenic deletion mutation in DSG4 gene in three Pakistani families with autosomal recessive hypotrichosis. J Invest Dermatol 123:247–248
Rafique MA, Ansar M, Jamal SM, Malik S, Sohail M, Faiyaz-Ul-Haque M, Haque S, Leal SM, Ahmad W (2003) A locus for hereditary hypotrichosis localized to human chromosome 18q21.1. Eur J Hum Genet 11:623–628
Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386
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 40:335–339
Shimomura Y, Agalliu D, Vonica A, Luria V, Wajid M, Baumer A, Belli S, Petukhova L, Schinzel A, Brivanlou AH, Barres BA, Christiano AM (2010) APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 464:1043–1047
Sobel E, Lange K (1996) Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am J Hum Genet 58:1323–1337
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 29:134–136
Tariq M, Ayub M, Jelani M, Basit S, Naz G, Wasif N, Raza SI, Naveed AK, ullah-Khan A, 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 160:1006–1010
van Steensel M, Smith FJ, Steijlen PM, Kluijt I, Stevens HP, Messenger A, Kremer H, Dunnill MG, Kennedy C, Munro CS, Doherty VR, McGrath JA, Covello SP, Coleman CM, Uitto J, McLean WH (1999) The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing. Am J Hum Genet 65:413–419
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 70:233–239
Wali A, Ali G, John P, Lee K, Chishti MS, Leal SM, Ahmad W (2007a) Mapping of a gene for alopecia with mental retardation syndrome (APMR3) on chromosome 18q11.2–q12.2. Ann Hum Genet 71:570–577
Wali A, Chishti MS, Ayub M, Yasinzai M, Kafaitullah Ali G, John P, Ahmad W (2007b) Localization of a novel autosomal recessive hypotrichosis locus (LAH3) to chromosome 13q14.11–q21.32. Clin Genet 72:23–29
Weeks DE, Sobel E, O’Connell JR, Lange K (1995) Computer programs for multilocus haplotyping of general pedigrees. Am J Hum Genet 56:1506–1507
Wen Y, Liu Y, Xu Y, Zhao Y, Hua R, Wang K, Sun M, Li Y, Yang S, Zhang XJ, Kruse R, Cichon S, Betz RC, Nöthen MM, van Steensel MA, van Geel M, Steijlen PM, Hohl D, Huber M, Dunnill GS, Kennedy C, Messenger A, Munro CS, Terrinoni A, Hovnanian A, Bodemer C, de Prost Y, Paller AS, Irvine AD, Sinclair R, Green J, Shang D, Liu Q, Luo Y, Jiang L, Chen HD, Lo WH, McLean WH, He CD, Zhang X (2009) Loss of function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nat Genet 41:228–233
Xu C, Zhang L, Chen N, Su B, Pan CM, Li JY, Zhang GW, Liu Z, Sheng Y, Song HD (2009) A new locus for hereditary hypotrichosis simplex maps to chromosome 13q12.12 approximately 12.3 in a Chinese family. J Cutan Pathol (in press)
Acknowledgments
We are grateful to all members of the family for their invaluable participation and cooperation. The work presented here was funded by Higher Education Commission (HEC), Islamabad, Pakistan. Sulman Basit was supported by indigenous PhD fellowships from HEC, Islamabad, Pakistan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Basit, S., Ali, G., Wasif, N. et al. 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, 213–220 (2010). https://doi.org/10.1007/s00439-010-0847-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-010-0847-y