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Hypotrichosis simplex of the scalp (HSS; OMIM 146520) is a rare, autosomal dominant form of nonsyndromic alopecia, characterized by progressive hair loss limited to the scalp. Affected individuals usually present with normal hair at birth and in early childhood, but experience loss of scalp hair beginning in the first decade of life and progressing to almost complete baldness by the third decade. The beard, eyebrows, eyelashes, axillary hair, body hair, teeth and nails are unaffected. HSS is caused by nonsense mutations in the corneodesmosin gene, CDSN, which leads to expression of a truncated protein probably toxic to hair growth.[1] We describe a Chinese family with HSS, in which we identified a novel nonsense mutation in the CDSN gene.

This was a large four-generation HSS family of Chinese Han ethnicity, comprising 14 affected family members (Fig. 1a). The proband was a 23-year-old woman who was born with normal scalp hair, but began to note the loss of scalp hair from the age of 12 years. The alopecia worsened to involve her whole scalp during her teenage years, although the hair loss became more stable after puberty. When examined, she was found to have sparse, thin and short hairs that were easily pulled out (Fig. 1b). Scanning electron microscopy of scalp hair showed an apparently normal hair shaft with slightly rough cuticle edges (Fig. 1c).

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Figure 1. (a) Pedigree of the family with HSS. The arrow indicates the proband, and the asterisks refer to the family members from whom blood samples were collected. (b) The proband had sparse, thin and short scalp hairs. (c) Under scanning electron microscopy, a scalp hair from the proband was seen to have slightly rough cuticle edges, but otherwise appeared normal. Original magnification × 1000; scale bar = 10 μm.

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The patient informed us that other members of her family had similar problems with hair loss. We therefore carried out an examination on other members of the family, and found that all those affected had nearly identical features. Vellus hair, eyebrows and eyelashes were unaffected, and the pubic and axillary hair (and beard hair in the men) developed normally during puberty. However, all affected members began experiencing hair loss at some point during their teenage years. None of the family members had a history of psoriasis or peeling skin syndrome.

Approval for a genetic study was given by the institutional review board, and informed consent was obtained from the proband for biopsy. Blood samples were collected from 16 family members (8 affected, 8 not affected; Fig. 1a), and a skin biopsy was taken from the proband's scalp.

Genomic DNA and total RNA were extracted from peripheral blood leucocytes and skin tissue, respectively. After removal of DNA with RNase-free DNase, mRNA was used as the template for synthesis of cDNA. PCR amplification was performed, and the products were purified and sequenced. For the proband, a heterozygous mutation c.625C>T was identified in the CDSN gene, which was predicted to result in a premature stop codon (p.Q209X) (Fig. 2). This mutation was found in all tested family members with HSS, but not in any of 200 unrelated normal DNA samples. Sequencing of cDNA showed a mutation peak (c.625T) equivalent to the wild-type (c.625C, data not shown), suggesting absence of marked nonsense-mediated decay of the mutant mRNA.

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Figure 2. Sequence chromatogram of the mutation c.625C>T in the corneodesmosin gene, CDSN, in the proband and a normal subject.

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CDSN codes for corneodesmosin, a late-differentiation epidermal glycoprotein specific to corneodesmosomes. CDSN is mainly expressed in the epidermis, the hard-palate epithelium, and the inner root sheath of hair follicles. All the mutations reported as responsible for HSS, including that identified here, were nonsense mutations located in a region between amino acids 200 and 239 (p.Q200X, p.Q215X, p.Y239X and p. Q209X).[2, 3] These mutations lead to a gradual accumulation of protein aggregates consisting of both truncated and full-length CDSN, which probably exerts a toxic effect on hair growth,[1] explaining the delayed onset of hair loss in HSS. Our PCR results using affected scalp tissue also support a dominant-negative effect, rather than haplotype insufficiency, being the underlying cause of HSS. In addition to HSS, polymorphisms in CDSN have also been associated with psoriasis,[4] and very recently, mutations in CDSN were shown to cause an autosomal recessive form of inflammatory PSS.[5] However, it remains to be elucidated why nonsense mutations in CDSN do not result in any hair anomaly in patients with PSS or obligate carriers.[5] Further studies are also needed to explain the confinement of alopecia to the scalp in HSS.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. References

We are grateful to the patient and her family members for their participation in this study. This work was supported by National Natural Science Foundation of China (81201220).

References

  1. Top of page
  2. Acknowledgements
  3. References
  • 1
    Levy-Nissenbaum E, Betz RC, Frydman M et al. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat Genet 2003; 34: 1513.
  • 2
    Davalos NO, Garcia-Vargas A, Pforr J et al. A nonsense mutation in the corneodesmosin gene in a Mexican family with hypotrichosis simplex of the scalp. Br J Dermatol 2005; 153: 121619.
  • 3
    Huang XS, Jiang HO, Quan QL. Clinical investigation of a Chinese family with hypotrichosis simplex of the scalp and mutational analysis of CDSN gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2012; 29: 4524.
  • 4
    Capon F, Allen MH, Ameen M et al. A synonymous SNP of the corneodesmosin gene leads to increased mRNA stability and demonstrates association with psoriasis across diverse ethnic groups. Hum Mol Genet 2004; 13: 23618.
  • 5
    Israeli S, Zamir H, Sarig O et al. Inflammatory peeling skin syndrome caused by a mutation in CDSN encoding corneodesmosin. J Invest Dermatol 2011; 131: 77981.