Genetics of Alopecia


A recent genome‐wide association study showed eight regions for alopecia areata (AA), including CTLA4, IL‐2/IL‐22, HLA‐class II, UL16‐binding protein‐3 and ‐6, syntaxin 17, IL‐2RA, peroxiredoxin 5 and Eos. Candidate genes associated with androgenetic alopecia are divided into androgen‐related and ‐unrelated genes. The former includes 5α‐reductase isozymes, androgen receptor and ectodysplasin A2 receptor, which is located close to androgen receptor (AR) gene, and possible AR coregulator such as histone deacetylase 9. The latter contains PAX1 and FOXA2. Regarding congenital hypotrichosis, mutations in EDA‐A1, EDAR and EDA‐RADD, p63 and P‐cadherin are pointed out for ectodermal dysplasia, SPINK5 for Netherton syndrome, desmoglein 4, lipase H (LIPH) and LPAR6 (P2RY5) for localised autosomal recessive hypotrichosis, lipase H (LIPH) and LPAR6 (P2RY5) for autosomal recessive woolly hair, keratin 74 for autosomal dominant woolly hair, corneodesmosin and APCDD for hypotrichosis simplex and hairless for Marie‐Unna hypotrichosis.

Key Concepts:

  • Recent studies using mainly genome‐wide association analysis revealed novel candidate genes associated with alopecia, providing informative explanation for the pathogenesis.

  • Genome‐wide association studies suggested the importance of innate and acquired immunity in alopecia areata pathogenesis and possibility of androgen‐independent pathogenic pathway in androgenetic alopecia.

  • Novel genes associated with congenital hypotrichosis have been found, providing new clues to search not only the pathogenesis but also molecular mechanism of normal hair growth.

Keywords: genetics; alopecia areata; androgenetic alopecia; ectodermal dysplasia; Netherton syndrome; localised autosomal recessive hypotrichosis; autosomal recessive woolly hair; autosomal dominant woolly hair; hypotrichosis simplex; Marie‐Unna hypotrichosis

Figure 1.

Molecular signalling pathway of androgen in the target cell. Testosterone can freely penetrate cellular membrane and enter into cytoplasm because the hormone is lipophilic. It is converted to more potent androgen dihydrotestosterone (DHT) by cytoplasmic 5α‐reductase. DHT strongly binds to AR located in the cytoplasm and the AR‐DHT dimer complex is translocated to the nucleus. The complex binds to the androgen‐response element, consensus sequence on DNA, resulting in target gene transcription. Reproduced with permission from the Japanese Dermatological Association.

Figure 2.

Mechanism of transcriptional regulation by nuclear receptor corepressors, which interact with histone deacetylases. The corepressors bridge between NR and histone deacetylases (HDACs), causing chromatin deacetylation and subsequently transcriptional inactivation. Reproduced with permission from the Japanese Dermatological Association.

Figure 3.

Signalling pathway of lipase H (LIPH)/lysophophatidic acid (LPA)/LPAR6 (P2RY5). Lipase H (LIPH) converts phophatidic acid (PA) into lysophophatidic acid (LPA), which binds its receptor LPAR6 (P2RY5), stimulating the essential signalling for hair growth. Reproduced with permission from the Japanese Dermatological Association.



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Further Reading

Al‐Owain M, Wakil S, Shareef F et al. (2011) Novel homozygous mutation in DSP causing skin fragility‐woolly hair syndrome: report of a large family and review of the desmoplakin‐related phenotypes. Clinical Genetics 80(1): 50–58.

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Petukhova L, Cabral RM, Mackay‐Wiggan J et al. (2011) The genetics of alopecia areata: what's new and how will it help our patients? Dermatologic Therapy 24(3): 326–336.

Shimomura Y and Christiano AM (2010) Biology and genetics of hair. Annual Review of Genomics and Human Genetics 22(11): 109–132.

Subramanya RD, Coda AB and Sinha AA (2010) Transcriptional profiling in alopecia areata defines immune and cell cycle control related genes within disease‐specific signatures. Genomics 96(3): 146–153.

Yip L, Rufaut N and Sinclair R (2011) Role of genetics and sex steroid hormones in male androgenetic alopecia and female pattern hair loss: an update of what we now know. Australasian Journal of Dermatology 52(2): 81–88.

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Inui, Shigeki(Apr 2012) Genetics of Alopecia. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023882]