title: Manitoba-oculo-tricho-anal (MOTA) syndrome is caused by mutations in FREM1.
abstract: 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.
  
  
  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.affiliation: Department of Pediatrics, Division of Genetics, University of California, 533 Parnassus Street, Room U585P, San Francisco, CA 94143-0748, USA. slavotia@peds.ucsf.edu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Slavotinek
authors.forename: Sergio E
authors.initials: SE
authors.lastname: Baranzini
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.forename: Cassandre
authors.initials: C
authors.lastname: Labelle-Dumais
authors.forename: Kieran M
authors.initials: KM
authors.lastname: Short
authors.forename: Ryan
authors.initials: R
authors.lastname: Chao
authors.forename: Mani
authors.initials: M
authors.lastname: Yahyavi
authors.forename: Emilia K
authors.initials: EK
authors.lastname: Bijlsma
authors.forename: Catherine
authors.initials: C
authors.lastname: Chu
authors.forename: Stacey
authors.initials: S
authors.lastname: Musone
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Wheatley
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Sandra
authors.initials: S
authors.lastname: Marles
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: A Murat
authors.initials: AM
authors.lastname: Maga
authors.forename: Mohamed G
authors.initials: MG
authors.lastname: Hassan
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.forename: Lohith
authors.initials: L
authors.lastname: Madireddy
authors.forename: Chumei
authors.initials: C
authors.lastname: Li
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Cox
authors.forename: Ian
authors.initials: I
authors.lastname: Smyth
authors.forename: Albert E
authors.initials: AE
authors.lastname: Chudley
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D001003:Anal Canal / Q000002:abnormalities / Q000473:pathology; D000818:Animals; D000071056:Anorectal Malformations; D001006:Anus, Imperforate / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003103:Coloboma / Q000235:genetics* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005143:Eyelids / Q000002:abnormalities; D005260:Female; D058497:Fraser Syndrome / Q000235:genetics* / Q000473:pathology; D018628:Gene Dosage; D006554:Hernia, Umbilical / Q000235:genetics / Q000473:pathology; D006801:Humans; D006972:Hypertelorism / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009666:Nose / Q000002:abnormalities; D009668:Nose Diseases / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D018123:Receptors, Interleukin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013577:Syndrome
chemical_list: D016326:Extracellular Matrix Proteins; C548979:Frem1 protein, human; C492585:Frem1 protein, mouse; D018123:Receptors, Interleukin