Review on genes involved in hereditary hypotrichosis

Paper Details

Review Paper 01/04/2019
Views (327) Download (8)

Review on genes involved in hereditary hypotrichosis

Zarmina Wali, Hasina Wali, Fazal-Ur-Rehman, Muhammad Ayub
Int. J. Biosci.14( 4), 123-134, April 2019.
Certificate: IJB 2019 [Generate Certificate]


In human, hair loss disorders are the heterogeneous group of genetic disorders. The characteristics of the genetic hair disorders are thin to complete loss of hair, but rarely on scalp has firmly twisted curled woolly hair been reported. Pattern of the hair loss is also in autosomal recessive or autosomal dominant form. The genes which are responsible for autosomal recessive heredity hypotrichosis are LIPH gene mapped on chromosome number 3q27.2 and Lysophosphatidic acid receptor 6, also known as LPAR6 gene which is located on chromosome number 13q14.2, Desmoglein-4 (DSG4) gene on chromosome number 18q12.1, Desmocollin-3 (DSC3) gene on chromosome number 18q12.1 and Hairless (HR) gene on chromosome number 8p21.3. There are also some autosomal dominant genes which are responsible for heredity hypotrichosis. In this review, several genes and different mutations of the hair disorders are discussed.


Azeem Z, Jelani M, Naz G, Tariq M, Wasif N, Naqvi SK, Ayub M, Yasinzai M, Wali A, Ali G, Chishti MS. 2008. Novel mutations in G protein-coupled receptor gene (P2RY5) in families with autosomal recessive hypotrichosis (LAH3). Human Genetics 123, 515-519.

Ayub M, Basit S, Jelani M, Rehman FU, Iqbal M, Yasinzai M, Ahmad W. 2009.  Homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles. The American Journal of Human Genetics 85, 515- 520.

Ahmad W, UlHaque MF, Brancolini V, Tsou HC, UlHaque S, Lam H, Aita VM, Owen J, Frank J, Cserhalmi-Friedman PB, Leask A. 1998. Alopecia universalis associated with a mutation in the human hairless gene. Journal of Science 279, 720- 724.

Ali G, Chishti MS, Raza SI, John P, Ahmad W. 2007. A mutation in the lipase H (LIPH) gene underlies autosomal recessive hypotrichosis. Human Genetics 121, 319- 325.

Amagai M, Nishikawa T, Wang Y. 1995. Assignment of the human genes for desmocollin 3 (DSC3) and desmocollin 4 (DSC4) to chromosome 18q12. Genomics 25, 330- 332.

Ahmad W. 1999. A homozygous nonsense mutation in the zinc-finger domain of the human hairless gene underlies congenital atrichia. Journal of investigative dermatology 113, 281- 283.

Basit S, Khan S, Ahmad W. 2015. Genetics of human isolated hereditary hair loss disorders. An international journal of Genetics, Molecular and Personalized Medicine 88, 203- 212.

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. Human genetics 128, 213- 220.

Bousquet-Antonelli C, Deragon JM. 2009.  A comprehensive analysis of the La-motif protein super family. A publication of the RNA society 15, 750-764.

Bazzi H, Getz A, Mahoney MG, Ishida-Yamamoto A, Langbein L, Wahl III JK, Christiano AM. 2006. Desmoglein 4 is expressed in highly differentiated keratinocytes and trichocytes in human epidermis and hair follicle. International Society of Differentiation 74, 129-140.

Buxton RS, Cowin P, Franke WW, Garrod DR, Green KJ, King IA, Koch PJ, Magee AI, Rees DA, Stanley JR. 1993. Nomenclature of the desmosomalcadherins. The Journal of Cell Biology 121, 481- 483.

Betz RC, Indelman M, Pforr J, Schreiner F, Bauer R, Bergman R, Lentze MJ, Nöthen MM, Cichon S, Sprecher E. 2007. Identification of mutations in the human hairless gene in two new families with congenital atrichia. Archives of dermatological research 299, 157-161.

Chartier MB, Hoss DM, Grant-Kels JM. 2002. Approach to the adult female patient with diffuse non scarring alopecia. Journal of the American Academy of Dermatology 47, 809-818.

Chien AJ, Valentine MC, Sybert VP. 2006. Hereditary woolly hair and keratosis  pilaris. Journal of the American Academy of Dermatology 54, S35-S39.

Cichon S, Anker M, Vogt IR, Rohleder H, Pützstück M, Hillmer A, Farooq SA, Al-Dhafri KS, Ahmad M, Haque S, Rietschel M. 1998. Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Human molecular genetics 7, 1671-1679.

Chidgey MA, Yue KK, Gould S, Byrne C, Garrod DR. 1997. Changing pattern of desmocollin 3 expression accompanies epidermal organisation during skin development. Developmental dynamics: an official publication of the American Association of Anatomists 210, 315-327.<315::AID-AJA11>3.0.CO;2-9

Cachon-Gonzalez MB, Fenner S, Coffin JM, Moran CH, Best ST, Stoye JP. 1994. Structure and expression of the hairless gene of mice. Proceedings of the National Academy of Science of United States of America 91, 7717-7721.

Delva E, Tucker DK, Kowalczyk AP. 2009. The desmosome. Cold Spring Harbor perspectives in biology 1, a002543.

Damsté TJ, Prakken JR. 1954. Atrichia with papular lesions; a variant of congenital ectodermal dysplasia. Dermatology 108, 114- 121.

Gilhar A, Kalish RS. 2006. Alopecia areata: a tissue specific autoimmune disease of the hair follicle. Autoimmunity reviews 5, 64-69.

García‐Hernández MJ, Ruiz‐Doblado S, Rodriguez‐Pichardo A, Camacho F. 1999. Alopecia areata, stress and psychiatric disorders: a review. The Journal of dermatology 26, 625-632.

Gossage AM. 1908. The inheritance of certain human abnormalities. QJM: An International Journal of Medicine 3, 331-347.

Grunwald GB. 1993. The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules. Current opinion in cell biology 5, 797- 805.

Hardy MH. 1992. The secret life of the hair follicle. Trends in Genetics 8, 55-61.

Hutchinson PE, Cairns RJ, Wells RS. 1974. Woolly hair. Clinical and general aspects. Transactions of the St. John’s Hospital Dermatological Society 60, 160-177.

Jelani M, Wasif N, Ali G, Chishti MS, Ahmad W. 2008. A novel deletion mutation in LIPH gene causes autosomal recessive hypotrichosis (LAH2). An international journal of Genetics, Molecular and Personalized Medicine 74, 184- 188.

John P, Tariq M, Rafiq MA, Muhammad D, Waheed I, Ansar M, Ahmad W. 2006. Recurrent intragenic deletion mutation in desmoglein 4 gene underlies autosomal recessive hypotrichosis in two Pakistani families of Balochi and Sindhi origins. Archives of dermatological research 298, 135-137.

Khalaf H, Negmi H, Hassan G, Al-Sebayel M. 2004. Postoperative alopecia areata: Is pressure-induced ischemia the only cause to blame? In Transplantation proceedings, Elsevier 36, 2158-2159.

Kljuic A, Bazzi H, Sundberg JP, Martinez-Mir A, O’Shaughnessy R, Mahoney MG, Levy M, Montagutelli X, Ahmad W, Aita VM, Gordon D. 2003. Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell press 113, 249- 260.

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.

Khan SA. 2016. Sequence to functional analysis of LPAR6 mutants using structural molecular models. Bioinformation 12, 430-435.

Kruse R, Cichon S, Anker M, Hillmer AM, Barros-Núñez P, Cantú JM, Leal E, Weinlich G, Schmuth M, Fritsch P, Ruzicka T. 1999. Novel hairless mutations in two kindreds with autosomal recessive papularatrichia. Journal of investigative dermatology 113, 954-959.

Kim H, Wajid M, Kraemer L, Shimomura Y, Christiano AM. 2007. Nonsense mutations in the hairless gene underlie APL in five families of Pakistani origin. Journal of dermatological science 48, 207-211.

Levy-Nissenbaum E, Betz RC, Frydman M, Simon M, Lahat H, Bakhan T, Goldman B, Bygum A, Pierick M, Hillmer AM, Jonca N. 2003. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nature genetics 34, 151-153.

Loewenthal LJ, Prakken JR. 1961. Atrichia with papular lesions. Dermatology 122, 85-89.

Madani S, Shapiro J. 2000. Alopecia areata update. Journal of the American Academy of Dermatology 42, 549- 566.

Matsuno N, Kunisada M, Kanki H, Simomura Y, Nishigori C. 2013. A case of autosomal recessive woolly hair/hypotrichosis with alternation in severity: deterioration and improvement with age. Case reports in dermatology 5, 363-367.

Norwood OT. 1975. Male pattern baldness: classification and incidence. Southern medical journal 68, 1359-1365.

Naz G, Ali G, Naqvi SK, Azeem Z, Ahmad W. 2010. Mapping of a novel autosomal recessive hypotrichosis locus on chromosome 10q11. 23–22.3. Human genetics 127, 395-401.

Nuber UA, Schäfer S, Stehr S, Rackwitz HR, Franke WW. 1996. Patterns of desmocollin synthesis in human epithelia: immunolocalization of desmocollins 1 and 3 in special epithelia and in cultured cells. European journal of cell biology 71, 1- 13.

Nöthen MM, Cichon S, Vogt IR, Hemmer S, Kruse R, Knapp M, Höller T, ulHaque MF, Haque S, Propping P, Ahmad M. 1998. A gene for universal congenital alopecia maps to chromosome 8p21-22. The American Journal of Human Genetics 62, 386-390.

Pasternack SM, Von Kügelgen I, Al Aboud K, Lee YA, Rüschendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, Nürnberg P. 2008. G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nature genetics 40, 329-334.

Pasternack SM, Refke M, Paknia E, Hennies HC, Franz T, Schäfer N, Fryer A, van Steensel M, Sweeney E, Just M, Grimm C. 2013. Mutations in SNRPE, which encodes a core protein of the spliceosome, cause autosomal-dominant hypotrichosis simplex. The American Journal of Human Genetics 92, 81-87.

Petukhova L, Sousa EC, Martinez-Mir A, Vitebsky A, dos Santos LG, Shapiro L, Haynes C, Gordon D, Shimomura Y, Christiano AM. 2008. Genome-wide linkage analysis of an autosomal recessive hypotrichosis identifies a novel P2RY5 mutation. Genomics 92, 273- 278.

Potter GB, Beaudoin GM, DeRenzo CL, Zarach JM, Chen SH, Thompson CC. 2001. The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes & development 15, 2687-2701.

Rosenquist TA, Martin GR. 1996. Fibroblast growth factor signalling in the hair growth cycle: expression of the fibroblast growth factor receptor and ligand genes in the murine hair follicle. Developmental dynamics: an official publication of the American Association of Anatomists 205, 379-386.<379::AID-AJA2>3.0.CO;2-F

Ruiz‐Doblado S, Carrizosa A, García‐Hernández MJ. 2003. Alopecia areata: psychiatric comorbidity and adjustment to illness. International journal of dermatology 42, 434-437.

Ramot Y, Zlotogorski A. 2015. The twisting tale of woolly hair: a trait with many causes. Journal of medical genetics 52, 217-223.

Schmitt JV, Ribeiro CF, Souza FH, Siqueira EB, Bebber FR. 2012. Hair loss perception and symptoms of depression in female outpatients attending a general dermatology clinic. The journal Brazilian Annals of Dermatology 87, 412- 417.

Shrivastava SB. 2009. Diffuse hair loss in an adult female: approach to diagnosis and management. Indian Journal of Dermatology, Venereology, and Leprology 75, 20-28.

Sawaya ME, Shapiro J. 2000. Androgenetic alopecia: new approved and unapproved treatments. Dermatologic clinics 18, 47-61.

Shapiro J, Price VH. 1998. Hair regrowth: therapeutic agents. Dermatologic clinics 16, 341-356.

Schokking CP. 1934. Another woolly-hair mutation in man. Journal of Heredity 25, 337-340.

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. Nature genetics 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. 2010a. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature, International journal of Science 464, 1043-1047.

Shimomura Y, Wajid M, Petukhova L, Kurban M, Christiano AM. 2010b. Autosomal-dominant woolly hair resulting from disruption of keratin 74 (KRT74), a potential determinant of human hair texture. The American Journal of Human Genetics 86, 632-638.

Sonoda H, Aoki J, Hiramatsu T, Ishida M, Bandoh K, Nagai Y, Taguchi R, Inoue K, Arai H. 2002. A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid. Journal of Biological Chemistry 277, 34254-34263.

Stavraka C, Blagden S. 2015. The La-related proteins, a family with connections to cancer. Biomolecules 5, 2701-2722.

Shinkuma S, Akiyama M, Inoue A, Aoki J, Natsuga K, Nomura T, Arita K, Abe R, Ito K, Nakamura H, Ujiie H. 2010. Prevalent LIPH founder mutations lead to loss of P2Y5 activation ability of PA‐PLA1α in autosomal recessive hypotrichosis. Human mutation 31, 602-610.

Schaffer JV, Bazzi H, Vitebsky A, Witkiewicz A, Kovich OI, Kamino H, Shapiro LS, Amin SP, Orlow SJ, Christiano AM. 2006. Mutations in the desmoglein 4 gene underlie localized autosomal recessive hypotrichosis with monilethrix hairs and congenital scalp erosions. Journal of investigative dermatology 126, 1286-1291.

Silos SA, Tamai K, Li K, Kivirikko S, Kouba D, Christiano AM, Uitto J. 1996. Cloning of the Gene for Human Pemphigus Vulgaris Antigen (Desmoglein 3), a Desmosomal Cadherin characterization of the promoter region and identification of a keratinocyte-specific cis-element. Journal of Biological Chemistry 271, 17504-17511.

Tosti A, Piraccini BM, Sisti A, Duque-Estrada B. 2009. Hair loss in women. Minerva ginecologica 61, 445-452.

Tocchetti A, Confalonieri S, Scita G, Di Fiore PP, Betsholtz C. 2003. In silico analysis of the EPS8 gene family: genomic organization, expression profile, and protein structure. Genomics 81, 234-244.

Theis DG, Koch PJ, Franke WW. 2003. Differential synthesis of type 1 and type 2 desmocollin mRNAs in human stratified epithelia. International Journal of Developmental Biology 37, 101- 110.

Thompson CC. 1996. Thyroid hormone-responsive genes in developing cerebellum include a novel synaptotagmin and a hairless homolog. Journal of Neuroscience 16, 7832-3840.

Tariq M, Ayub M, Jelani M, Basit S, Naz G, Wasif N, Raza SI, Naveed AK, Ullah Khan S, Azeem Z, Yasinzai M. 2009. Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families. British Journal of Dermatology 160, 1006-1010.

Wen Y, Liu Y, Xu Y, Zhao Y, Hua R, Wang K, Sun M, Li Y, Yang S, Zhang XJ, Kruse R. 2009. Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nature genetics 41, 228- 233.

Wasserman D, Guzman‐Sanchez DA, Scott K, McMichael A. 2007. Alopecia areata. International journal of dermatology 46, 121-131.

Whiting DA. 1987. Structural abnormalities of the hair shaft. Journal of the American Academy of Dermatology 16, 1-25.

Wajid M, Bazzi H, Rockey J, Lubetkin J, Zlotogorski A, Christiano AM. 2007. Localized autosomal recessive hypotrichosis due to a frameshift mutation in the desmoglein 4 gene exhibits extensive phenotypic variability within a Pakistani family. The Journal of investigative dermatology 127, 1779-1782.

Whittock NV, Bower C. 2003. Genetic evidence for a novel human desmosomal cadherin, desmoglein 4. Journal of investigative dermatology 120, 523- 530.

Yip L, Horev L, Sinclair R, Zlotogorski A.  2008. Atrichia with papular lesions: a report of three novel human hairless gene mutations and a revision of diagnostic criteria. Actadermato-venereologica 88, 346- 349.

Zlotogorski A, Marek D, Horev L, Abu A, Ben-Amitai D, Gerad L, Ingber A, Frydman M, Reznik-Wolf H, Vardy DA, Pras E. 2006. An autosomal recessive form of monilethrix is caused by mutations in DSG4: clinical overlap with localized autosomal recessive hypotrichosis. Journal of investigative dermatology 126, 1292- 1296.

Zlotogorski A, Martinez-Mir A, Green J, Lam H, Panteleyev AA, Sinclair R, Christiano AM. 2002a. Evidence for pseudodominant inheritance of atrichia with papular lesions. Journal of investigative dermatology 118, 881-886.

Zlotogorski A, Panteleyev AA, Aita VM, Christiano AM. 2002b. Clinical and Molecular Diagnostic Criteria of Congenital Atrichia with Papular Lesions1. Journal of investigative dermatology 118, 887-890