In humans, mutations in FRAS1 cause Fraser Syndrome (FS), a pleiotropic condition with many clinical presentations such as limb, eye, kidney, and craniofacial deformations.
It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes.
Here we report the first case of a family with two patients affected by Fraser syndrome due to a deletion of 64 kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene.
Here we report the first case of a family with two patients affected by Fraser syndrome due to a deletion of 64 kb (deletion 4q21.21) and an additional novel frameshift mutation in exon 66 of the FRAS1 gene.
Deficiency of the extracellular matrix molecule FRAS1, normally expressed by the ureteric bud, leads to bilateral renal agenesis in humans with Fraser syndrome and blebbed (Fras1(bl/bl)) mice.
Lesions in the epithelially expressed human gene FRAS1 cause Fraser syndrome, a complex disease with variable symptoms, including facial deformities and conductive hearing loss.
Recessive truncating mutations in FRAS1 and FREM2 were known to cause Fraser syndrome in humans and mice; however, a phenotype in heterozygous carriers has not been described.
Recently, a novel group of basement membrane proteins, Fras1 (Fraser syndrome protein (1) and the Fras1-related extracellular matrix proteins Frem1, Frem2 and Frem3, has emerged.
The milder phenotypes associated with FREM1 deficiency in humans (MOTA syndrome and BNAR syndrome) compared to that resulting from FRAS1 and FREM2 loss of function (Fraser syndrome) are also consistent with the less severe phenotypes resulting from Frem1 loss of function in mice.
FS is considered to be the human equivalent of the murine blebbing mutants: in the mouse mutations at five loci cause a phenotype that is comparable to FS in humans, and thus far mutations in two syntenic human genes, FRAS1 and FREM2, have been identified to cause FS.
Molecular diagnostic studies of the index case failed to identify one of the known gene mutations in the FRAS1 and FREM2 genes associated with Fraser syndrome.
Extensive studies on mRNA expression indicated that this mutation most likely leads to loss of function as most previously reported FRAS1 mutations associated with FS.
Extensive studies on mRNA expression indicated that this mutation most likely leads to loss of function as most previously reported FRAS1 mutations associated with FS.
We have screened two patients who fulfilled the diagnostic criteria for Fraser syndrome and three patients with related phenotypes (two patients with Manitoba oculotrichoanal syndrome and one patient with unilateral cryptophthalmos and labial fusion) for mutations in FRAS1 to increase the molecular genetic data in patients with Fraser syndrome and related conditions.
Our results showed that p.Arg2167Trp had a weaker effect in interrupting interactions between FREM2 and FREM1 than FS-associated missense mutation p.Glu1972Lys.
Of the candidate genes, four genes (i.e., ITGA8, GRIP1, FREM1, and FREM2) were Fraser syndrome-related genes, encoding proteins that functionally converged on the glial cell-derived neurotrophic factor/RET/bone morphogenic protein (BMP) signaling pathways.
It overlaps clinically with Fraser syndrome (FS; OMIM 219000), which is known to be caused by mutations in either FRAS1, FREM2, or GRIP1, encoding components of a protein complex that plays a role in epidermal-dermal interactions during morphogenetic processes.