A family with hypothyroidism caused by fatty acid synthase and apolipoprotein B receptor mutations

Abstract

Hypothyroidism is a disease with a genetic component. The present study aimed to identify the potential causative gene mutation in a family with hypothyroidism and to investigate its potential pathology. DNA was extracted from the affected individual and his parents, maternal aunt and maternal grandmother. Whole exome sequencing was used to examine their exomes. The potential causative genes that may have an autosomal dominant mode of inheritance were selected after variant calling and filtering. Bioinformatics analysis was utilized to predict the deleteriousness of the identified variants, and multiple sequence alignment and conserved protein domain analyses were performed using online software. Finally, Sanger sequencing was used to validate the identified variants. In the present study, a total of 50 variants were screened based on the autosomal dominant mode of inheritance. Two variants, the fatty acid synthase (FASN) and apolipoprotein B receptor (APOBR) genes, were further analyzed, as they were highly associated with hypothyroidism. Genotyping results revealed that two mutations, c.G7192T (p.A2398S) in the FASN gene and c.C1883G (p.T628R) in the APOBR gene, were fully co‑segregated with established hypothyroidism phenotypes in the family. These mutations were located in the conserved α/β‑hydrolase fold and Na+/Ca2+ exchanger superfamily domain of FASN and APOBR, respectively. In conclusion, the present study demonstrated that the FASN c.G7192T and APOBR c.C1883G mutations may be the potential causative variants in this Chinese hypothyroidism pedigree.

Keywords: WES; hypothyroidism; FASN; APOBR.

Figure 1.

Hypothyroidism pedigree. Exome sequencing was performed on individuals IV:1, III:1, III:2, III:3 and II:3. IV:1 was identified as the proband; I:1 and II:1 were individuals with subclinical hypothyroidism; II:5 was a probable case of hypothyroidism. Circles represent female individuals; squares represent male individuals. W, whole exome sequencing.

Figure 2.

(A) Affected amino acid residue was highly conserved between different species. (B) Conserved domains in fatty acid synthase.

Figure 3.

(A) Affected amino acid residue was highly conserved between different species. (B) Conserved domains in apolipoprotein B receptor.

Figure 4.

Sanger validation results of fatty acid synthase variants in ten family members of the hypothyroidism pedigree. Arrow represents the mutation site.

Figure 5.

Sanger validation results of apolipoprotein B receptor variants in ten family members of the hypothyroidism pedigree. Arrow represents the mutation site.