CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.
Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic "molar tooth sign" (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS.
INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
Soumaya
S
Mougou-Zerelli
Sophie
S
Thomas
Emmanuelle
E
Szenker
Sophie
S
Audollent
Nadia
N
Elkhartoufi
Candice
C
Babarit
Stéphane
S
Romano
Rémi
R
Salomon
Jeanne
J
Amiel
Chantal
C
Esculpavit
Marie
M
Gonzales
Estelle
E
Escudier
Bruno
B
Leheup
Philippe
P
Loget
Sylvie
S
Odent
Joëlle
J
Roume
Marion
M
Gérard
Anne-Lise
AL
Delezoide
Suonavy
S
Khung
Sophie
S
Patrier
Marie-Pierre
MP
Cordier
Raymonde
R
Bouvier
Jéléna
J
Martinovic
Marie-Claire
MC
Gubler
Nathalie
N
Boddaert
Arnold
A
Munnich
Férechté
F
Encha-Razavi
Enza Maria
EM
Valente
Ali
A
Saad
Sophie
S
Saunier
Michel
M
Vekemans
Tania
T
Attié-Bitach
D000483:Alleles; D015331:Cohort Studies; D003598:Cytoskeletal Proteins; D018507:Gene Expression Regulation, Developmental; D005808:Genes, Recessive; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D009154:Mutation; D009422:Nervous System Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D013577:Syndrome
C528701:CC2D2A protein, human; D003598:Cytoskeletal Proteins; D011506:Proteins