Identification of a novel compound heterozygous mutation and a homozygous mutation of SLURP1 in Chinese families with Mal de Meleda

Abstract

Background: Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family.

Methods: We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis.

Results: Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL.

Conclusions: Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.

Keywords: Mal de Meleda; Mutation analysis; SLURP1.

Fig. 1

Clinical manifestations and pedigree of patients. a Pedigree of proband 1. Arrow represents the proband, square represents male, and circle represents female. b Palmoplantar keratoderma in proband 1 (P1). c-d Mild hyperkeratotic and erythematous plaques involve the palms and soles with scales. e Pedigree of proband 2, who was the only affected individual in a consanguineous family. f-h Yellow keratoderma and erythema involve dorsa of the hands and feet. Hyperhidrosis and maceration appear on the palms and soles

Fig. 2

Missense mutations of SLURP1. a P1(II-1): a compound heterozygous mutation c.243C > A, c.256G > A. P1 father (I-1): a heterozygous mutation c.243C > A. P1 mother (I-2): a heterozygous mutation c.256G > A. b P2 (IV-2): a homozygous mutation c.211C > T. P2 father (III-1): a heterozygous mutation c.211C > T. P2 mother (III-2): a heterozygous mutation c.211C > T. Normal human control for mutations were shown

Fig. 3

Conservation of the local amino acid sequence by multiple alignment of SLURP1 from different species. R71C, D81E and G86R are highly conservative positions

Fig. 4

The impacts of SLURP1 mutations on the molecular structure of protein. a AlphaFold2 predicted the wild type and mutated protein crystal structure (domain in smudge). The hydrogen bonds were shown by yellow lines. The unit of the distances was Å. b Ramachandran plots of mutated proteins were provided