Mutation Screening and Functional Study of in Chinese Patients with Congenital Hypothyroidism.

Objective: Defects in the human solute carrier family 26 member 4 () gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify mutations in Chinese patients with CH and analyze the function of the mutations.

Methods: Patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing. All the exons and exon-intron boundaries of were identified and analyzed. The function of six missense mutation in were further investigated .

Results: Among 273 patients with CH, seven distinct heterozygous mutations (p.S49R, p.I363L, p.R409H, p.T485M, p.D661E, p.H723R, c.919-2A>G) were identified in 10 patients (3.66%, 10/273). In vitro experiments showed that mutation p.I363L, p.R409H, p.H723R affect the membrane location and ion transport of , while p.S49R did not. Mutation p.T485M and p.D661E only affected ion transport, but had no effect on the membrane location.

Conclusion: The prevalence of mutations was 3.66% in Chinese patients with CH. Five mutations (p.I363L, p.R409H, p.T485M, p.D661E and p.H723R) impaired the membrane location or ion transport function of , suggesting important roles for Ile363, Arg409, Thr485, Asp661, and His723 residues in function. As all variants identified were heterozygous, the pathogenesis of these patients cannot be explained, and the pathogenesis of these patients needs further study.