title: A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24.
abstract: Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus ( MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 ( Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 ( Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families.
authors.affiliation: Section of Medical and Molecular Genetics, Department of Paediatrics and Child Health, University of Birmingham Medical School, Birmingham, B15 2TT, UK.
authors.forename: Neil V
authors.initials: NV
authors.lastname: Morgan
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.forename: Saghira Malik
authors.initials: SM
authors.lastname: Sharif
authors.forename: Laura
authors.initials: L
authors.lastname: Baumber
authors.forename: Joan
authors.initials: J
authors.lastname: Sutherland
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Kelly
authors.forename: Kingi
authors.initials: K
authors.lastname: Aminu
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Bennett
authors.forename: C Geoffrey
authors.initials: CG
authors.lastname: Woods
authors.forename: Robert F
authors.initials: RF
authors.lastname: Mueller
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Eamonn R
authors.initials: ER
authors.lastname: Maher
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D008297:Male; D008565:Membrane Proteins; D009436:Neural Tube Defects / Q000235:genetics; D010375:Pedigree; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D008565:Membrane Proteins; D011506:Proteins; C468846:TMEM67 protein, human