Novel SOS1 Mutations Associated With Hereditary Gingival Fibromatosis and Dual-Gated Model for SOS1 Activation.

BACKGROUND

Hereditary gingival fibromatosis (HGF) is a rare, genetically heterogeneous disorder characterized by benign, slowly progressive fibrous overgrowth of the gingiva. This study aimed to identify the pathogenic genes responsible for non-syndromic HGF and to elucidate the activation mechanism for truncated SOS1 protein.

METHODS

Genomic DNA was extracted from peripheral blood samples of two unrelated Han Chinese families with non-syndromic HGF. Whole-genome sequencing (WGS) was utilized to identify pathogenic mutations. Bioinformatic analyses were conducted to predict the deleteriousness of the identified mutations. The phenotypic spectrum of SOS1 mutations was summarized by literature review methods, with a particular focus on the gingival hyperplasia phenotype. Genotype-phenotype correlations were analyzed.

RESULTS

WGS identified two novel SOS1 mutations, c.3262dupA/p.Thr1088fs and c.1523A>G/p.Asn508Ser in two unrelated Han Chinese families with non-syndromic HGF. MutationTaster and CADD revealed the c.1523A>G/p.Asn508Ser mutation as disease-causing. The mutational spectrum of SOS1 showed a predominance of missense mutations, among which three were linked to the gingival hyperplasia phenotype. Frameshift mutations in the C-terminal region of SOS1 were all associated with the gingival hyperplasia phenotype. A novel "Dual-Gated Model" was introduced to elucidate the activation mechanisms for both the normal and truncated forms of SOS1.

CONCLUSIONS

Our study identified two novel SOS1 mutations, c.3262dupA/p.Thr1088fs and c.1523A>G/p.Asn508Ser, in two unrelated Han Chinese families with non-syndromic HGF. A novel "Dual-Gated Model" was proposed to elucidate the full activation process of wild-type and truncated SOS1. We extended the mutational spectrum of SOS1 in non-syndromic HGF and provided new insights on the molecular mechanism of pathogenesis.