title: Inverted formin 2 mutations with variable expression in patients with sporadic and hereditary focal and segmental glomerulosclerosis.
abstract: Focal and segmental glomerulosclerosis (FSGS) is a major cause of end-stage kidney disease. Recent advances in molecular genetics show that defects in the podocyte play a major role in its pathogenesis and mutations in inverted formin 2 (INF2) cause autosomal dominant FSGS. In order to delineate the role of INF2 mutations in familial and sporadic FSGS, we sought to identify variants in a large cohort of patients with FSGS. A secondary objective was to define an approach for genetic screening in families with autosomal dominant disease. A total of 248 individuals were identified with FSGS, of whom 31 had idiopathic disease. The remaining patients clustered into 64 families encompassing 15 from autosomal recessive and 49 from autosomal dominant kindreds. There were missense mutations in 8 of the 49 families with autosomal dominant disease. Three of the detected variants were novel and all mutations were confined to exon 4 of INF2, a regulatory region responsible for 90% of all changes reported in FSGS due to INF2 mutations. Thus, in our series, INF2 mutations were responsible for 16% of all cases of autosomal dominant FSGS, with these mutations clustered in exon 4. Hence, screening for these mutations may represent a rapid, non-invasive and cost-effective method for the diagnosis of autosomal dominant FSGS.
authors.affiliation: Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. michelle.winn@duke.edu
authors.forename: Rasheed A
authors.initials: RA
authors.lastname: Gbadegesin
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lavin
authors.forename: Gentzon
authors.initials: G
authors.lastname: Hall
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Bartkowiak
authors.forename: Alison
authors.initials: A
authors.lastname: Homstad
authors.forename: Ruiji
authors.initials: R
authors.lastname: Jiang
authors.forename: Guanghong
authors.initials: G
authors.lastname: Wu
authors.forename: Alison
authors.initials: A
authors.lastname: Byrd
authors.forename: Kelvin
authors.initials: K
authors.lastname: Lynn
authors.forename: Norman
authors.initials: N
authors.lastname: Wolfish
authors.forename: Carolina
authors.initials: C
authors.lastname: Ottati
authors.forename: Paul
authors.initials: P
authors.lastname: Stevens
authors.forename: David
authors.initials: D
authors.lastname: Howell
authors.forename: Peter
authors.initials: P
authors.lastname: Conlon
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Winn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D005091:Exons; D005260:Female; D000080865:Formins; D005799:Genes, Dominant; D005808:Genes, Recessive; D005820:Genetic Testing; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007223:Infant; D008297:Male; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins; D050505:Mutant Proteins