Zhongguo shi yan xue ye xue za zhi · 2026
[Clinical Phenotype and Molecular Pathogenesis of a Hereditary Hemochromatosis Family with Double-Site Mutations in SLC40A1].
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Hou Chuan-Dong, Geng Jie, Zhang Ya-Jing, Zhao Peng, He Tian-Tian, Zhang Hui, Li Hong-Yi, Zhang Hao-Jun, Zhang Li-Zhong, Gao Chu-Meng, Lu Xue-Chun
Аннотация
OBJECTIVE: To investigate the clinical phenotype and molecular pathogenesis of a hereditary hemochromatosis family with double-site mutations in SLC40A1 .
METHODS: High-throughput exome sequencing was performed to screen for gene mutations, and Sanger sequencing was used to validate the suspected mutations in SLC40A1 . The pathogenicity of the variants was predicted using bioinformatics tools including PROVEAN, FATHMM, and MutPred2. The amino acid conservation was analyzed using Mega software, and the mutated protein models were simulated with PyMol software.
RESULTS: The proband and his two twin daughters had significantly elevated serum ferritin levels, while his wife was normal. Genetic testing revealed that the proband and his two twin daughters had heterozygous missense mutations c.94C>T (p.His32Tyr) in exon 2 and c.431A>C (p.Asn144Thr) in exon 5 of SLC40A1 . The wife did not carry any mutations in the SLC40A1 gene. Bioinformatics analysis suggested that p.His32Tyr and p.Asn144Thr were pathogenic mutations, and the related amino acid sites were highly conserved across seven species. Protein modeling showed that the His32Tyr substitution caused the loss of the hydrogen bond between His32 and Asp181 and the formation of an additional hydrogen bond with Gln155, significantly affecting the protein's spatial conformation. The p.Asn144Thr mutation did not cause significant structural abnormalities in the protein.
CONCLUSION: The missense mutations c.94C>T (p.His32Tyr) and c.431A>C (p.Asn144Thr) in SLC40A1 are likely responsible for the iron overload in the proband and may represent the genetic cause of primary hemochromatosis.
METHODS: High-throughput exome sequencing was performed to screen for gene mutations, and Sanger sequencing was used to validate the suspected mutations in SLC40A1 . The pathogenicity of the variants was predicted using bioinformatics tools including PROVEAN, FATHMM, and MutPred2. The amino acid conservation was analyzed using Mega software, and the mutated protein models were simulated with PyMol software.
RESULTS: The proband and his two twin daughters had significantly elevated serum ferritin levels, while his wife was normal. Genetic testing revealed that the proband and his two twin daughters had heterozygous missense mutations c.94C>T (p.His32Tyr) in exon 2 and c.431A>C (p.Asn144Thr) in exon 5 of SLC40A1 . The wife did not carry any mutations in the SLC40A1 gene. Bioinformatics analysis suggested that p.His32Tyr and p.Asn144Thr were pathogenic mutations, and the related amino acid sites were highly conserved across seven species. Protein modeling showed that the His32Tyr substitution caused the loss of the hydrogen bond between His32 and Asp181 and the formation of an additional hydrogen bond with Gln155, significantly affecting the protein's spatial conformation. The p.Asn144Thr mutation did not cause significant structural abnormalities in the protein.
CONCLUSION: The missense mutations c.94C>T (p.His32Tyr) and c.431A>C (p.Asn144Thr) in SLC40A1 are likely responsible for the iron overload in the proband and may represent the genetic cause of primary hemochromatosis.