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.
Mougou-Zerelli
Soumaya
S
INSERM U-781, Hôpital Necker-Enfants Malades, Paris, France.
Thomas
Sophie
S
Szenker
Emmanuelle
E
Audollent
Sophie
S
Elkhartoufi
Nadia
N
Babarit
Candice
C
Romano
Stéphane
S
Salomon
Rémi
R
Amiel
Jeanne
J
Esculpavit
Chantal
C
Gonzales
Marie
M
Escudier
Estelle
E
Leheup
Bruno
B
Loget
Philippe
P
Odent
Sylvie
S
Roume
Joëlle
J
Gérard
Marion
M
Delezoide
Anne-Lise
AL
Khung
Suonavy
S
Patrier
Sophie
S
Cordier
Marie-Pierre
MP
Bouvier
Raymonde
R
Martinovic
Jéléna
J
Gubler
Marie-Claire
MC
Boddaert
Nathalie
N
Munnich
Arnold
A
Encha-Razavi
Férechté
F
Valente
Enza Maria
EM
Saad
Ali
A
Saunier
Sophie
S
Vekemans
Michel
M
Attié-Bitach
Tania
T
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