Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1

Department of Pediatrics, Division of Genetics, University of California, 533 Parnassus Street, Room U585P, San Francisco, CA 94143-0748, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 06/2011; 48(6):375-82. DOI: 10.1136/jmg.2011.089631
Source: PubMed


Manitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance had been assumed because of consanguinity in the Oji-Cre population of Manitoba and reports of affected siblings, but no locus or cytogenetic aberration had previously been described.
This study shows that MOTA syndrome is caused by mutations in FREM1, a gene previously mutated in bifid nose, renal agenesis, and anorectal malformations (BNAR) syndrome. MOTA syndrome and BNAR syndrome can therefore be considered as part of a phenotypic spectrum that is similar to, but distinct from and less severe than, Fraser syndrome. Re-examination of Frem1(bat/bat) mutant mice found new evidence that Frem1 is involved in anal and craniofacial development, with anal prolapse, eyelid colobomas, telecanthus, a shortened snout and reduced philtral height present in the mutant mice, similar to the human phenotype in MOTA syndrome.
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. Together, Fraser, BNAR and MOTA syndromes constitute a clinically overlapping group of FRAS-FREM complex diseases.

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Available from: Timothy C Cox
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    • "In mice, mutations of Fras1, Frem1, Frem2, and Grip1 cause a so called " blebbed " phenotype [Smyth and Scambler, 2005]. Mutations of FREM1 in humans have recently been observed in two disorders, BNAR and MOTA syndrome, that overlap with each other as well as with FS though being clinically distinguishable from the latter [Alazami et al., 2009; Slavotinek et al., 2011]. Together these observations have established a group of FRAS–FREM complex disorders in humans that includes FS, BNAR, MOTA, and presumably also AMS. "
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    ABSTRACT: Ablepharon macrostomia syndrome (AMS; OMIM 200110) is an extremely rare congenital malformation syndrome. 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. We explored the hypothesis that AMS might be either allelic to FS or caused by mutations in other genes encoding known FRAS1 interacting partners. No mutation in either of these genes was found in a cohort of 11 patients with AMS from 10 unrelated families. These findings demonstrate that AMS is genetically distinct from FS. It is proposed that it constitutes a separate entity within the group of FRAS-FREM complex disorders. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Dec 2013 · American Journal of Medical Genetics Part A
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    • "Anal stenosis and anteriorly placed anus are among the anorectal anomalies seen in individuals with FREM1 deficiency [19]–[21]. While we found no evidence for anal stenosis in studies of fecal diameter, we show that male Frem1eyes2/eyes2 mice on a C57BL6 background have decreased anogenital distances. "
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    ABSTRACT: The FRAS1-related extracellular matrix 1 (FREM1) gene encodes an extracellular matrix protein that plays a critical role in the development of multiple organ systems. In humans, recessive mutations in FREM1 cause eye defects, congenital diaphragmatic hernia, renal anomalies and anorectal malformations including anteriorly placed anus. A similar constellation of findings-microphthalmia, cryptophthalmos, congenital diaphragmatic hernia, renal agenesis and rectal prolapse-have been described in FREM1-deficient mice. In this paper, we identify a homozygous Frem1 missense mutation (c.1687A>T, p.Ile563Phe) in an N-ethyl-N-nitrosourea (ENU)-derived mouse strain, crf11, with microphthalmia, cryptophthalmos, renal agenesis and rectal prolapse. This mutation affects a highly conserved residue in FREM1's third CSPG domain. The p.Ile563Phe change is predicted to be deleterious and to cause decreased FREM1 protein stability. The crf11 allele also fails to complement the previously described eyes2 allele of Frem1 (p.Lys826*) providing further evidence that the crf11 phenotype is due to changes affecting Frem1 function. We then use mice bearing the crf11 and eyes2 alleles to identify lung lobulation defects and decreased anogenital distance in males as novel phenotypes associated with FREM1 deficiency in mice. Due to phenotypic overlaps between FREM1-deficient mice and mice that are deficient for the retinoic acid-responsive transcription factor GATA4 and the extracellular matrix protein SLIT3, we also perform experiments to look for in vivo genetic interactions between the genes that encode these proteins. These experiments reveal that Frem1 interacts genetically with Gata4 in the development of lung lobulation defects and with Slit3 in the development of renal agenesis. These results demonstrate that FREM1-deficient mice faithfully recapitulate many of the phenotypes seen in individuals with FREM1 deficiency and that variations in GATA4 and SLIT3 expression modulate some FREM1-related phenotypes in mice.
    Full-text · Article · Mar 2013 · PLoS ONE
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    • "MOTA syndrome was initially described by Marles et al.7 in Aboriginal patients of the Island Lake region of Northern Manitoba, Canada. MOTA syndrome is so rare that only ten cases have been reported until now9-11. The pattern of inheritance is not clear but is thought to have an autosomal recessive basis. "
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    ABSTRACT: A wedge-shaped anterior hairline extension is a very rare skin manifestation usually associated with congenital anomalies including a Tessier number 10 cleft. Other associated conditions are the Tessier number 9 cleft, the Fraser syndrome, and the Manitoba oculotrichoanal syndrome (MOTA syndrome). The Tessier number 10 cleft features include a coloboma of the middle third of the upper eyelid, and an eyebrow divided into two portions. The medial eyebrow portion may be absent and the lateral portion is angulated vertically, joining the hairline of the scalp. This creates a wedge-shaped anterior hairline extension. Herein we report on a case of a wedge-shaped anterior hairline extension associated with the Tessier number 10 cleft.
    Full-text · Article · Nov 2012 · Annals of Dermatology
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