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CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype–phenotype correlation
Author(s) -
MougouZerelli Soumaya,
Thomas Sophie,
Szenker Emmanuelle,
Audollent Sophie,
Elkhartoufi Nadia,
Babarit Candice,
Romano Stéphane,
Salomon Rémi,
Amiel Jeanne,
Esculpavit Chantal,
Gonzales Marie,
Escudier Estelle,
Leheup Bruno,
Loget Philippe,
Odent Sylvie,
Roume Joëlle,
Gérard Marion,
Delezoide AnneLise,
Khung Suonavy,
Patrier Sophie,
Cordier MariePierre,
Bouvier Raymonde,
Martinovic Jéléna,
Gubler MarieClaire,
Boddaert Nathalie,
Munnich Arnold,
EnchaRazavi Férechté,
Valente Enza Maria,
Saad Ali,
Saunier Sophie,
Vekemans Michel,
AttiéBitach Tania
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21116
Subject(s) - joubert syndrome , biology , polydactyly , missense mutation , genetics , agenesis , ciliopathies , phenotype , cilium , gene
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. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.