Case Report: A Missense Mutation in Dyskeratosis Congenita 1 Leads to a Benign Form of Dyskeratosis Congenita Syndrome With the Mucocutaneous Triad

Abstract

Background: Dyskeratosis congenita (DC) is a rare inheritable disorder characterized by bone marrow failure and mucocutaneous triad (reticular skin pigmentation, nail dystrophy, and oral leukoplakia). Dyskeratosis congenita 1 (DKC1) is responsible for 4.6% of the DC with an X-linked inheritance pattern. Almost 70 DKC1 variations causing DC have been reported in the Human Gene Mutation Database.

Results: Here we described a 14-year-old boy in a Chinese family with a phenotype of abnormal skin pigmentation on the neck, oral leukoplakia, and nail dysplasia in his hands and feet. Genetic analysis and sequencing revealed hemizygosity for a recurrent missense mutation c.1156G > A (p.Ala386Thr) in DKC1 gene. The heterozygous mutation (c.1156G > A) from his mother and wild-type sequence from his father were obtained in the same site of DKC1. This mutation was determined as disease causing based on silico software, but the pathological phenotypes of the proband were milder than previously reported at this position (HGMDCM060959). Homology modeling revealed that the altered amino acid was located near the PUA domain, which might affect the affinity for RNA binding.

Conclusion: This DKC1 mutation (c.1156G > A, p.Ala386Thr) was first reported in a Chinese family with mucocutaneous triad phenotype. Our study reveals the pathogenesis of DKC1 c.1156G > A mutation to DC with a benign phenotype, which expands the disease variation database, the understanding of genotype-phenotype correlations, and facilitates the clinical diagnosis of DC in China.

Keywords: DKC1; c.1156G > A; dyskeratosis congenita syndrome; missense mutation; p.Ala386Thr.

FIGURE 1

Clinical features of the proband and pedigree, sequencing analysis, and DKC1 mutation investigations. Pigmentation on the neck (A), mucosal leukoplakia on the tongue (B), finger nail ridging, toenail ridging, and longitudinal splitting (C–F) in the proband. (G) The pedigree of the family. The arrow indicates the proband. (H) Sequencing chromatograms show the proband with a hemizygous mutation DKC1 c.1156G > A, the proband’s mother with the same heterozygous mutation; the black arrow indicates the position of the nucleotide mutation. (I) A linear representation of the DKC1 protein shows the location of the N-terminal nuclear localization signals (NLS), DKCLD, TruB_N, and PUA domains. The black arrow shows the positions of the amino acid substitutions. (J) The mutant site (c.1156G > A) of DKC1 is highly conserved phylogenetically among the indicated species. (K) The mutant proteins were structured by the Swiss-Model online software and compared with the wild type. Ribbon representation of the human DKC1 and map of the studied variant localization obtained by homology modeling analysis. The wild-type and mutant monomers are shown in black; DKCLD, TruB_N, and PUA domains are shown in blue, orange, and green, respectively. Amino acid Ala386 is shown as red.