PMC9019361_01
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.
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F1
Three affected males (III-6, IV-2, and IV-3) and 14 unaffected individuals are involved in this family and are recruited from Shanxi Province, China (Figure 1G). IV-2 is a 14-year-old boy with abnormal skin pigmentation on the neck (Figure 1A), oral leukoplakia (Figure 1B), and nail dysplasia on his hands and feet (Figures 1C-F). Peripheral blood samples were collected from this family, which includes three individuals (III-2, III-3, and IV-2); a recurrent DKC1 hemizygous mutation (c.1156G > A) in exon 12 was confirmed in the proband (IV-2) by using Sanger sequencing (Figure 1H). Furthermore, a heterozygous mutation (c.1156G > A) in his mother (III-2) and a wild-type sequence in his father (III-3) were obtained on the same site of DKC1 (Figure 1H). Evolutionary conservation of amino acid residue showed that the impaired amino acid residues Ala386 were highly conserved in different species (Figure 1J). DKC1 shows that the missense mutation was concentrated near the PUA domain (Figures 1I,K), which is crucial for the RNA binding of telomerase. DKC1 mutations concentrated in or near the PUA domain decrease the affinity for RNA binding.