title: FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.
abstract: An autosomal-recessive syndrome of bifid nose and anorectal and renal anomalies (BNAR) was previously reported in a consanguineous Egyptian sibship. Here, we report the results of linkage analysis, on this family and on two other families with a similar phenotype, which identified a shared region of homozygosity on chromosome 9p22.2-p23. Candidate-gene analysis revealed homozygous frameshift and missense mutations in FREM1, which encodes an extracellular matrix component of basement membranes. In situ hybridization experiments demonstrated gene expression of Frem1 in the midline of E11.5 mouse embryos, in agreement with the observed cleft nose phenotype of our patients. FREM1 is part of a ternary complex that includes FRAS1 and FREM2, and mutations of the latter two genes have been reported to cause Fraser syndrome in mice and humans. The phenotypic variability previously reported for different Frem1 mouse mutants suggests that the apparently distinct phenotype of BNAR in humans may represent a previously unrecognized variant of Fraser syndrome.
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
authors.forename: Anas M
authors.initials: AM
authors.lastname: Alazami
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Fatema
authors.initials: F
authors.lastname: Alzahrani
authors.forename: Katie
authors.initials: K
authors.lastname: Snape
authors.forename: Anand
authors.initials: A
authors.lastname: Saggar
authors.forename: Bernd
authors.initials: B
authors.lastname: Brinkmann
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.forename: Lihadh I
authors.initials: LI
authors.lastname: Al-Gazali
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009297:Nasal Mucosa / Q000378:metabolism; D009666:Nose / Q000196:embryology; D013577:Syndrome
chemical_list: D016326:Extracellular Matrix Proteins; C492585:Frem1 protein, mouse