title: Aberrant splicing is a common mutational mechanism in MKS1, a key player in Meckel-Gruber syndrome.
abstract: Meckel-Gruber syndrome (MKS) is an autosomal recessive, usually lethal multisystemic disorder characterized by early developmental anomalies of the central nervous system, cystic kidney dysplasia, hepatobiliary ductal plate malformation, and postaxial polydactyly. Three MKS loci have been mapped and recently, two genes were identified: MKS1 on 17q22 in Caucasian kindreds and MKS3 on 8q22 in Omani and Pakistani families, putting MKS on the growing list of ciliary disorders ("ciliopathies"). We performed linkage analysis for MKS1-3 in 14 consanguineous and/or multiplex families of different ethnic origins with histologic diagnosis and at least three classic MKS manifestations in each kindred. Unexpectedly, only five families were linked to any of the known MKS loci, clearly indicating further locus heterogeneity. All five families showed homozygosity for MKS1 and, intriguingly, were of non-Caucasian origin. MKS1 sequencing revealed no mutation in two of these pedigrees, whereas different, novel splicing defects were identified in the three other families and an additional sporadic German patient. Given that all of our mutations and two of the in total four known MKS1 changes cause aberrant splicing (while the other two known mutations were frameshift mutations), we hypothesize that splicing defects are a crucial mutational mechanism in MKS1 which apparently is one of the main loci and key players in MKS. Our results indicate that MKS1 mutations are not restricted to the Caucasian gene pool and suggest further genetic heterogeneity for MKS. Overall, our data have immediate implications for genetic counselling and testing approaches in MKS.
authors: Department of Human Genetics, RWTH Aachen University, Aachen, Germany.
authors: Valeska
authors: V
authors: Frank
authors: Nadina
authors: N
authors: Ortiz Brüchle
authors: Silke
authors: S
authors: Mager
authors: Susanna G M
authors: SG
authors: Frints
authors: Axel
authors: A
authors: Bohring
authors: Gabriele
authors: G
authors: du Bois
authors: Irmgard
authors: I
authors: Debatin
authors: Heide
authors: H
authors: Seidel
authors: Jan
authors: J
authors: Senderek
authors: Nesrin
authors: N
authors: Besbas
authors: Unda
authors: U
authors: Todt
authors: Christian
authors: C
authors: Kubisch
authors: Tiemo
authors: T
authors: Grimm
authors: Fulya
authors: F
authors: Teksen
authors: Sevim
authors: S
authors: Balci
authors: Klaus
authors: K
authors: Zerres
authors: Carsten
authors: C
authors: Bergmann
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D017398:Alternative Splicing; D002490:Central Nervous System / Q000002:abnormalities*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005091:Exons; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007438:Introns; D052177:Kidney Diseases, Cystic / Q000235:genetics*; D007730:Kuwait; D008099:Liver / Q000002:abnormalities; D009154:Mutation; D010375:Pedigree; D017689:Polydactyly / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion; D013577:Syndrome; D014421:Turkey; D044465:White People / Q000235:genetics
chemical_list: C509165:MKS1 protein, human; D011506:Proteins