TY - JOUR
T1 - CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation
AU - Mougou-Zerelli, Soumaya
AU - Thomas, Sophie
AU - Szenker, Emmanuelle
AU - Audollent, Sophie
AU - Elkhartoufi, Nadia
AU - Babarit, Candice
AU - Romano, Stéphane
AU - Salomon, Rémi
AU - Amiel, Jeanne
AU - Esculpavit, Chantal
AU - Gonzales, Marie
AU - Escudier, Estelle
AU - Leheup, Bruno
AU - Loget, Philippe
AU - Odent, Sylvie
AU - Roume, Joëlle
AU - Gérard, Marion
AU - Delezoide, Anne Lise
AU - Khung, Suonavy
AU - Patrier, Sophie
AU - Cordier, Marie Pierre
AU - Bouvier, Raymonde
AU - Martinovic, Jéléna
AU - Gubler, Marie Claire
AU - Boddaert, Nathalie
AU - Munnich, Arnold
AU - Encha-Razavi, Férechté
AU - Valente, Enza Maria
AU - Saad, Ali
AU - Saunier, Sophie
AU - Vekemans, Michel
AU - Attié-Bitach, Tania
PY - 2009/11
Y1 - 2009/11
N2 - 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.
AB - 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.
KW - CC2D2A
KW - Ciliopathy
KW - JBS
KW - Joubert syndrome
KW - Meckel-Gruber syndrome
KW - MKS
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U2 - 10.1002/humu.21116
DO - 10.1002/humu.21116
M3 - Article
C2 - 19777577
AN - SCOPUS:70350719356
VL - 30
SP - 1574
EP - 1582
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 11
ER -