Whole‑exome sequencing identifies a novel mutation of SLC20A2 (c.C1849T) as a possible cause of hereditary multiple exostoses in a Chinese family

Abstract

although the main causative genes for hereditary multiple exostoses (HMe) are exostosin (EXT)-1 and EXT-2, there are numerous patients with HMe without EXT-1 and EXT-2 mutations. The present study aimed to identify novel candidate genes for the development of HMe in patients without EXT-1 and EXT-2 mutations. Whole-exome sequencing was performed in a chinese family with HMe and without EXT-1 and EXT-2 mutations, followed by a combined bioinformatics pipeline including annotation and filtering processes to identify candidate variants. candidate variants were then validated using Sanger sequencing. a total of 1,830 original variants were revealed to be heterozygous mutations in three patients with HMe which were not present in healthy controls. Two mutations [c.c1849T in solute carrier family 20 member 2 (Slc20a2) and c.G506a in leucine zipper and eF-hand containing transmembrane protein 1 (leTM1)] were identified as possible causative variants for HME through a bioinformatics filtering procedure and harmful prediction. Sanger sequencing results confirmed these two mutations in all patients with HME. A mutation in Slc20a2 (c.c1849T) led to a change in an amino acid (p.r617c), which may be involved in the development of HMe by inducing metabolic disorders of phosphate and abnormal proliferation and differentiation in chondrocytes. in conclusion, the present study revealed two mutations [Slc20a2 (c.c1849T) and leTM1 (c.G506a) in a chinese family with HMe. The mutation in Slc20a2 (c.c1849T)] was more likely to be involved in the development of HMe.

A mutation in SLC20A2 (c.C1849T) promotes proliferation while inhibiting hypertrophic differentiation in ATDC5 chondrocytes

“…Our previous study showed that the mutation of SLC20A2 (c.C1849T) was at the highly conserved amino acid sequences, at which a mutation might have a great probability to induce structural and functional changes. 10 Other studies have also reported severe Pi transport impairment in cells with SLC20A2 mutations. 30,34,35 In particular, in the study by Taglia et al 30 mentioned above, although the authors did not find significant changes in PiT-2 expression in SLC20A2 mutant cells, they observed significantly reduced Pi uptake, which may be attributed to altered PiT-2 subcellular localization in cells with the SLC20A2 mutation.…”

“…The mutation of SLC20A2 (c.C1849T) was identified by whole-exome sequencing in a Chinese family with HME without EXT-1 and EXT-2 mutations. 10 The proband (age, four years; sex, male) sought medical advice at our hospital due to multiple exostoses at the bilateral distal femur, proximal tibia and fibula, distal tibia, proximal humerus, and left scapula. The mother and grandfather of the proband were also diagnosed with HME.…”

“…In our recent study, we performed whole-exome sequencing in a typical Chinese HME family without EXT-1 and EXT-2 mutations and identified a novel mutation of the solute carrier family 20 member 2 ( SLC20A2 ) gene (c.C1849T). 10 As a member of the SLC20 family of solute carriers, the SLC20A2 protein (PiT-2) comprises 652 amino acids, and its molecular mass is 70,392 Da. 11 PiT-2 is expressed ubiquitously in all tissues and is considered as a 'housekeeping' transport protein.…”

“…In theory, mutation in SLC20A2 (c.C1849T) may lead to a change in the amino acid sequence (p.R617C) ( Figures 1c and 1d ), 10 which might induce structural changes and dysfunction of PiT-2, subsequently leading to a disturbance of Pi homeostasis in cells.…”