Two novel mutations in VPS33B gene cause a milder ARC syndrome with prolonged survival in a 12-year-old patient: Case report

Abstract

Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare autosomal recessive disease caused by VPS33B and VIPAR gene mutations. The main clinical manifestations are congenital joint contracture, renal dysfunction mainly characterized by distal renal tubular dysfunction, and low glutamyltransferase cholestasis. Most patients with ARC die within 2 years of birth. Here, we report the case of a 12-year-old girl with an ARC phenotype who experienced long-term survival with only mild clinical symptoms. We detected two new heterozygous mutation sites of the VPS33B gene in this child, c.1081C > T (p.GLN361X, 257) and c.244T > C (p.Cys82Arg), through the gene detection technique; the tertiary structure of the protein was predicted by using the SWISS-model. We further reviewed the literature and summarized the clinical manifestations and gene loci of 19 ARC syndrome patients with long-term survival reported so far.

Keywords: ARC syndrome; VPS33B; genetics; novel mutation; prolonged survival.

Figure 1

Clinical symptoms. (A) Joint contracture can be seen in the finger and toe joints of the patient. (B) The patient has dry skin and hand and foot desquamation, which is the manifestation of ichthyosis. (C) The patient has a yellow skin stain all over the body, accompanied by icteric sclera.

Figure 2

The whole exon gene sequencing showing two novel heterozygous mutations in VPSS33B gene. (A) The first mutation is c1081(exon14)C > T, NM_018668, p.Q361X,257, which originated from the patient's mother. (B) The second mutation is c.244(exon4)T > C, NM_018668, p.C82R, which originated from the patient's father.

Figure 3

Genetic analysis and illustration of the heterozygous c1081C > T and c.244T > C mutation of VPSS33B gene. (A) VPS33B protein secondary structure; p.Q361X, 257 and p.C82R are located in the Sec1 domain. (B) VPS33B protein 3D structure (wild-type global image): Gln361(red) and Cys82 (pink). (C) VPS33B protein 3D structure (mutant global image); termination of amino acid translation at position 361 of VPS33B protein, resulting in the loss of 257 amino acids and truncated protein. (D) VPS33B protein 3D structure (wild-type local image); Cys82 (pink) forms a hydrogen bond with Leu29 (red) and Leu30 (yellow); the red arrow points to the hydrogen bond (yellow dotted line). (E) VPS33B protein 3D structure (mutant local image); Arg82 (pink) forms a hydrogen bond with Leu29 (red), Leu30 (yellow), Asp38 (orange), and Phe40 (green), respectively; the red arrow points to the hydrogen bond (yellow dotted line). Compared with the wild type, the number of hydrogen bonds has increased and the protein conformation has changed. (F) Conservation analysis of VPS33B protein; Gln361 and Cys82 are located in the highly conserved amino acid region, and the conserved amino acid mutation may damage the protein function.