Aim
To analyze the role of SPTLC1 mutation on adult-onset T2D with strong family history.
Background
Although numerous single nucleotide polymorphism in multiple genes involve in the risk of type 2 diabetes mellitus (T2D), the single gene defects of T2D with strong family history is not clear yet. SPTLC1 are causative for hereditary sensory and autonomic neuropathy, which is clinical overlapping with diabetic peripheral neuropathy. Mice with adipocyte-specific deletion of SPTLC1 had impaired glucose tolerances and insulin sensitivity. Thus, it is necessary to investigate the SPTLC1 mutations in adult-onset T2D with strong family history.
Conclusion
The study classified SPTLC1 p.G371R mutation as the likely pathogenic mutation from an adult-onset T2D patients with strong family history T2D.
Methods
By whole-exome sequence analysis of a patient with T2D and his family members, an uncertain variant in SPTLC1 was identified. Bioinformation analysis was used to evaluate the influence of mutation, rare variant gene-level associations for SPTLC1 in T2D, and the relationship between SPTLC1 mRNA and T2D in human islets from GSE25724. The effect of G371R of SPTLC1 on the characteristics of inflammatory cytokines and apoptosis was also tested on human embryonic kidney (HEK) 293 cells.
Results
A single nucleotide variation in SPTLC1 (c.1111G>A: p.G371R) was identified in a family with T2D. The deleterious variant was predicted by functional analysis through hidden Markov models and mendelian clinically applicable pathogenicity software. This pathogenicity might be derived from the different amino acid properties. In HEK 293T cells, p.G371R of SPTLC1 induced the expression of tumor necrosis factor-α and the percent of apoptosis. Meanwhile, rare variant gene-level associations for SPTLC1 also refer to the high risk of T2D (the overall odds ratio = 2.4968, P = 0.0164). Data from GSE25724 showed that SPTLC1 mRNA was lower in pancreatic islets from T2D human islets (P = 0.046), and was associated with the decreased level of insulin mRNA expression (Spearman r = 0.615, P = 0.025).