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Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate

Jezewski, PA and Vieira, AR and Nishimura, C and Ludwig, B and Johnson, M and O'Brien, SE and Daack-Hirsch, S and Schultz, RE and Weber, A and Nepomucena, B and Romitti, PA and Christensen, K and Orioli, IM and Castilla, EE and Machida, J and Natsume, N and Murray, JC (2003) Complete sequencing shows a role for MSX1 in non-syndromic cleft lip and palate. Journal of Medical Genetics, 40 (6). 399 - 407. ISSN 0022-2593

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MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes cleftinq as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and sequence highly conserved elements. The samples studied were drawn from a panethnic collection including people of European, Asian and native South American ancestry. The gene was sequenced in 917 people and potentially aetiological mutations were identified in 16. These included missense mutations in conserved amino acids and point mutations in conserved regions not identified in any of 500 controls sequenced. Five different missense mutations in seven unrelated subjects with clefting are described. Evolutionary sequence comparisons of all known Msx1 orthologues placed the amino acid substitutions in context. Four rare mutations were found in non-coding regions that are highly conserved and disrupt probable regulatory regions. In addition a panel of 18 population specific polymorphic variants were identified that will be useful in future haplotype analyses of MSX1. MSX1 mutations are found in 2% of cases of clefting and should be considered for genetic counsellinq implications, particularly in those families in which autosomal dominant inheritance patterns or dental anomalies appear to be cosegregating with the clefting phenotype.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Jezewski, PA
Vieira, ARarv11@pitt.eduARV11
Nishimura, C
Ludwig, B
Johnson, M
O'Brien, SE
Daack-Hirsch, S
Schultz, RE
Weber, A
Nepomucena, B
Romitti, PA
Christensen, K
Orioli, IM
Castilla, EE
Machida, J
Natsume, N
Murray, JC
Date: 1 June 2003
Date Type: Publication
Journal or Publication Title: Journal of Medical Genetics
Volume: 40
Number: 6
Page Range: 399 - 407
DOI or Unique Handle: 10.1136/jmg.40.6.399
Schools and Programs: School of Dental Medicine > Dental Science
Refereed: Yes
ISSN: 0022-2593
MeSH Headings: Amino Acid Sequence--genetics; Animals; Asia; Case-Control Studies; Cattle; Chickens--genetics; Cleft Lip--genetics; Cleft Palate--genetics; DNA--genetics; DNA Mutational Analysis--methods; Europe; Genetic Variation--genetics; Genetics, Population--methods; Homeodomain Proteins--chemistry; Homeodomain Proteins--genetics; Homeodomain Proteins--physiology; Humans; Linkage Disequilibrium--genetics; MSX1 Transcription Factor; Mice; Molecular Sequence Data; Mutation--genetics; Polymorphism, Genetic--genetics; Rats; Sequence Alignment--methods; South America; Syndrome; Transcription Factors--chemistry; Transcription Factors--genetics; Transcription Factors--physiology; Untranslated Regions--genetics; Xenopus Proteins--genetics
Other ID: NLM PMC1735501
PubMed Central ID: PMC1735501
PubMed ID: 12807959
Date Deposited: 18 Sep 2012 14:55
Last Modified: 19 Jul 2020 10:55


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