BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Authors: Anne M Slavotinek; Ali Moshrefi; Randy Davis; Elizabeth Leeth; G Bradley Schaeffer; González Esteban Burchard; Gary M Shaw; Bristow James; Louis Ptacek; Len A Pennacchio Journal: Eur J Hum Genet Date: 2006-05-31 Impact factor: 4.246
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Authors: Chumei Li; Sandra L Marles; Cheryl R Greenberg; Bernard N Chodirker; Jiddeke van de Kamp; Anne Slavotinek; Albert E Chudley Journal: Am J Med Genet A Date: 2007-04-15 Impact factor: 2.802
Authors: Jared Coffin Talbot; Macie B Walker; Thomas J Carney; Tyler R Huycke; Yi-Lin Yan; Ruth A BreMiller; Linda Gai; April Delaurier; John H Postlethwait; Matthias Hammerschmidt; Charles B Kimmel Journal: Development Date: 2012-08 Impact factor: 6.868
Authors: Tyler F Beck; Danielle Veenma; Oleg A Shchelochkov; Zhiyin Yu; Bum Jun Kim; Hitisha P Zaveri; Yolande van Bever; Sunju Choi; Hannie Douben; Terry K Bertin; Pragna I Patel; Brendan Lee; Dick Tibboel; Annelies de Klein; David W Stockton; Monica J Justice; Daryl A Scott Journal: Hum Mol Genet Date: 2012-12-05 Impact factor: 6.150
Authors: Jared Nathanson; Daniel T Swarr; Amihood Singer; Mochi Liu; Amy Chinn; Wendy Jones; Jane Hurst; Nahla Khalek; Elaine Zackai; Anne Slavotinek Journal: Am J Med Genet A Date: 2013-02-08 Impact factor: 2.802