FREM1 mutations cause bifid nose, renal agenesis, and anorectal malformations syndrome.
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.
Alazami
Anas M
AM
Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia.
Shaheen
Ranad
R
Alzahrani
Fatema
F
Snape
Katie
K
Saggar
Anand
A
Brinkmann
Bernd
B
Bavi
Prashant
P
Al-Gazali
Lihadh I
LI
Alkuraya
Fowzan S
FS
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
D016326:Extracellular Matrix Proteins; C492585:Frem1 protein, mouse