title: A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1.
abstract: Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1) and chromosome 5q13-q22 (HGF2). To identify the gene responsible for HGF1, we extended genetic linkage studies to refine the chromosome 2p21-p22 candidate interval to approximately 2.3 Mb. Development of an integrated physical and genetic map of the interval identified 16 genes. Sequencing of these genes, in affected and unaffected HGF1 family members, identified a mutation in the Son of sevenless-1 (SOS1) gene in affected individuals. In this report, we describe the genomic structure of the SOS1 gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene is responsible for HGF1. This insertion mutation, which segregates in a dominant manner over four generations, introduces a frameshift and creates a premature stop codon, abolishing four functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. The resultant protein chimera contains the wild-type SOS1 protein for the N-terminal amino acids 1-1083 fused to a novel 22-amino acid carboxyl terminus. Similar SOS1 deletion constructs are functional in animal models, and a transgenic mouse construct with a comparable SOS1 chimera produces a phenotype with skin hypertrophy. Clarification of the functional role of this SOS1 mutant has implications for understanding other forms of gingival fibromatosis and corrective gingival-tissue management.
authors.affiliation: Center For Craniofacial and Dental Genetics, Division of Oral Biology and Pathology, University of Pittsburgh School of Dental Medicine, 614 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, USA. hart@sdmgenetics.pitt.edu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Hart
authors.forename: Yingze
authors.initials: Y
authors.lastname: Zhang
authors.forename: Michael C
authors.initials: MC
authors.lastname: Gorry
authors.forename: P Suzanne
authors.initials: PS
authors.lastname: Hart
authors.forename: Margaret
authors.initials: M
authors.lastname: Cooper
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: Jared M
authors.initials: JM
authors.lastname: Marks
authors.forename: Jose R
authors.initials: JR
authors.lastname: Cortelli
authors.forename: Debora
authors.initials: D
authors.lastname: Pallos
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D001938:Brazil; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005351:Fibromatosis, Gingival / Q000145:classification* / Q000235:genetics*; D005799:Genes, Dominant / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D007438:Introns / Q000235:genetics; D008126:Lod Score; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D020161:Physical Chromosome Mapping; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D020837:SOS1 Protein / Q000737:chemistry / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D020837:SOS1 Protein