title: Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.
abstract: Meckel syndrome (MKS) is a rare autosomal recessive lethal condition characterized by central nervous system malformations (typically occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. MKS is genetically heterogeneous and three loci have been mapped respectively on 17q23 (MKS1), 11q13 (MKS2), and 8q24 (MKS3). Very recently, two genes have been identified: MKS1/FLJ20345 on 17q in Finnish kindreds, carrying the same intronic deletion, c.1408-35_c.1408-7del29, and MKS3/TMEM67 on 8q in families from Pakistan and Oman. Here we report the genotyping of the MKS1 and MKS3 genes in a large, multiethnic cohort of 120 independent cases of MKS. Our first results indicate that the MKS1 and MKS3 genes are each responsible for about 7% of MKS cases with various mutations in different populations. A strong phenotype-genotype correlation, depending on the mutated gene, was observed regarding the type of central nervous system malformation, the frequency of polydactyly, bone dysplasia, and situs inversus. The MKS1 c.1408-35_1408-7del29 intronic mutation was identified in three cases from French or English origin and dated back to 162 generations (approx. 4050 years) ago. We also identified a common MKS3 splice-site mutation, c.1575+1G>A, in five Pakistani sibships of three unrelated families of Mirpuri origin, with an estimated age-of-mutation of 5 generations (125 years).
authors.affiliation: INSERM U-781, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France.
authors.forename: Rana
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authors.lastname: Khaddour
authors.forename: Ursula
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authors.lastname: Smith
authors.forename: Lekbir
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authors.lastname: Baala
authors.forename: Jéléna
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authors.lastname: Martinovic
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authors.lastname: Clavering
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authors.lastname: Shaffiq
authors.forename: Catherine
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authors.forename: Mira
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authors.lastname: Kyttälä
authors.forename: Stavit
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authors.lastname: Shalev
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authors.forename: Camille
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authors.lastname: d'Humières
authors.forename: Noman
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authors.forename: Chantal
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authors.lastname: Esculpavit
authors.forename: Géraldine
authors.initials: G
authors.lastname: Viot
authors.forename: Claire
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authors.lastname: Boone
authors.forename: Christine
authors.initials: C
authors.lastname: Oien
authors.forename: Férechté
authors.initials: F
authors.lastname: Encha-Razavi
authors.forename: Philip A
authors.initials: PA
authors.lastname: Batman
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bennett
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Joelle
authors.initials: J
authors.lastname: Roume
authors.forename: Stanislas
authors.initials: S
authors.lastname: Lyonnet
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Génin
authors.forename: Martine
authors.initials: M
authors.lastname: Le Merrer
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Phillip
authors.initials: P
authors.lastname: Cox
authors.forename: Fiona
authors.initials: F
authors.lastname: Macdonald
authors.forename: Michel
authors.initials: M
authors.lastname: Vekemans
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.forename: Tania
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authors.lastname: Attié-Bitach
mesh_terms: D002493:Central Nervous System Diseases / Q000235:genetics*; D015331:Cohort Studies; D005006:Ethnicity; D005838:Genotype; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: C509165:MKS1 protein, human; D008565:Membrane Proteins; D011506:Proteins; C468846:TMEM67 protein, human