Genetics of Isolated Hereditary Nail Disorder


Recent advances in molecular genetics and emergence of next‐generation genomic tools have led to the identification of many genes expressed in nail matrix/bed. However, the precise roles of these genes in the nail development and regeneration have not completely been disclosed. Using the methods of forward genetics, a series of genes responsible for hereditary nail disorders have recently been identified. Furthermore, expression and functional analyses have gradually revealed that these genes are directly or indirectly related with each other. This article briefly discusses the clinical and genetic perspective on defining and classifying isolated hereditary nail disorders and the overlapping genetic pathways. The journey towards unravelling the molecular basis of hereditary nail disorders will contribute to better understanding of the complex mechanisms for nail morphogenesis and development in humans.

Key Concepts

  • Genetic and non‐genetic factors contribute to nail diseases.
  • Hereditary nail disorders may exist as an isolated entity or associated with other diseases.
  • Underlying genes in nail disorders and signalling pathways in nail development can provide a logical basis for the classification of genetic disorders of nail.
  • To date, mutations in five genes have been identified as a cause of isolated hereditary nail disorders.
  • Development of nail unit requires epithelial–mesenchymal interactions.
  • Wnt signalling pathway is crucial for maintaining epithelial–mesenchymal interaction.
  • Lipid biosynthesis is required for the development and maintenance of proper nail structure.

Keywords: nail; genetics; isolated nail disorders; FZD6; RSPO4; PLCD1; SCLO2A1; SLC25A16; HPGD

Figure 1. An individual showing an anonychia phenotype. Note the reduction in nail field size, absence of nail plates in toes (a). Phenotype showing onychauxis, hyponychia and onycholysis in both fingernails (b). Reprinted from Khan, S., Basit, S., Habib, R., Kamal, A., Muhammad, N. and Ahmad, W. (2015), Genetics of human isolated hereditary nail disorders. Br J Dermatol, 173: 922–929.
Figure 2. Clinical photographs of both hands and feet showing whitish coloured nails (Leukonychia). Reprinted from Khan, S., Basit, S., Habib, R., Kamal, A., Muhammad, N. and Ahmad, W. (2015), Genetics of human isolated hereditary nail disorders. Br J Dermatol, 173: 922–929.
Figure 3. Pure fingernail dysplasia phenotypes caused by mutation in gene SLC25A16. Affected member showing keratotic lesions and thickening of the nail plate, onychodystrophy and swelling of the fingers (a). Clinical features of affected family member with mutation in SLCO2A1. Nail clubbing of hands is evident (b). Shah, K., Ferrara, T.M., Jan, A., Umair, M., Irfanullah, Khan, S., Ahmad, W. and Spritz, R.A. (2017), Homozygous SLCO2A1 translation initiation codon mutation in a Pakistani family with recessive isolated congenital nail clubbing. Br J Dermatol with permission from John Wiley & Sons.
Figure 4. Fingernails of affected individual presenting onycholysis. Toenails of the same individual showing anonychia (a). Reprinted from Rafiq, M., Ansar, M., Pham, T., Amin‐ud‐din, M., Anwar, M., Haque, S., Chahrour, M., Yan, K., Leal, S. and Ahmad, W. (2004), Localization of a novel locus for hereditary nail dysplasia to chromosome 17q25.1‐17q25.3. Clinical Genetics, 66: 73–78. Fingernails show thinning and longitudinal streaks. Some lunulae are poorly developed. The nail plates of the thumbs are striated and seem to broaden distally by overgrowing the lateral nail folds (b).
Figure 5. Activation of β‐catenin‐dependent TCF/LEF transcription by Wnt signalling. The β‐catenin‐dependent signalling pathway is initiated by association of Wnt with the FZD and LRP‐5/6 receptors. This association activates Dishevelled, which subsequently recruits the Axin protein complex. Kinases in Axin complex phosphorylate LRP5/6 and the entire protein complex lead to the accumulation and translocation of β‐catenin to the nucleus, where it associates with TCF/LEF family transcription factors and co‐activators, to induce the expression of Wnt target genes.


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Further Reading

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Wilson NJ, O'Toole EA, Milstone LM, et al. (2014) The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol 171 (2): 343–355.

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Basit, Sulman(Sep 2017) Genetics of Isolated Hereditary Nail Disorder. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027247]