Spectrum of MKS1 and MKS3 mutations in Meckel syndrome: a genotype-phenotype correlation. Mutation in brief #960. Online.
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).
Khaddour
Rana
R
INSERM U-781, Hôpital Necker-Enfants Malades, Université René Descartes, Paris, France.
Smith
Ursula
U
Baala
Lekbir
L
Martinovic
Jéléna
J
Clavering
Davina
D
Shaffiq
Rizwana
R
Ozilou
Catherine
C
Cullinane
Andrew
A
Kyttälä
Mira
M
Shalev
Stavit
S
Audollent
Sophie
S
d'Humières
Camille
C
Kadhom
Noman
N
Esculpavit
Chantal
C
Viot
Géraldine
G
Boone
Claire
C
Oien
Christine
C
Encha-Razavi
Férechté
F
Batman
Philip A
PA
Bennett
Christopher P
CP
Woods
C Geoffrey
CG
Roume
Joelle
J
Lyonnet
Stanislas
S
Génin
Emmanuelle
E
Le Merrer
Martine
M
Munnich
Arnold
A
Gubler
Marie-Claire
MC
Cox
Phillip
P
Macdonald
Fiona
F
Vekemans
Michel
M
Johnson
Colin A
CA
Attié-Bitach
Tania
T
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
C509165:MKS1 protein, human; D008565:Membrane Proteins; D011506:Proteins; C468846:TMEM67 protein, human