The transmembrane protein meckelin (MKS3) is mutated in Meckel-Gruber syndrome and the wpk rat.
Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.
Smith
Ursula M
UM
Section of Medical and Molecular Genetics, Division of Reproductive and Child Health, University of Birmingham Medical School, Birmingham B15 2TT, UK.
Consugar
Mark
M
Tee
Louise J
LJ
McKee
Brandy M
BM
Maina
Esther N
EN
Whelan
Shelly
S
Morgan
Neil V
NV
Goranson
Erin
E
Gissen
Paul
P
Lilliquist
Stacie
S
Aligianis
Irene A
IA
Ward
Christopher J
CJ
Pasha
Shanaz
S
Punyashthiti
Rachaneekorn
R
Malik Sharif
Saghira
S
Batman
Philip A
PA
Bennett
Christopher P
CP
Woods
C Geoffrey
CG
McKeown
Carole
C
Bucourt
Martine
M
Miller
Caroline A
CA
Cox
Phillip
P
Algazali
Lihadh
L
Trembath
Richard C
RC
Torres
Vicente E
VE
Attie-Bitach
Tania
T
Kelly
Deirdre A
DA
Maher
Eamonn R
ER
Gattone
Vincent H
VH
Harris
Peter C
PC
Johnson
Colin A
CA
D000015:Abnormalities, Multiple / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009436:Neural Tube Defects / Q000235:genetics; D010375:Pedigree; D020161:Physical Chromosome Mapping; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains / Q000235:genetics*; D017208:Rats, Wistar; D013577:Syndrome
D005819:Genetic Markers; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; C468846:TMEM67 protein, human