TY - JOUR
T1 - FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation
AU - Meloni, Ilaria
AU - Muscettola, Maddalena
AU - Raynaud, Martine
AU - Longo, Ilaria
AU - Bruttini, Mirella
AU - Moizard, Marie Pierre
AU - Gomot, Marie
AU - Chelly, Jamel
AU - Des Portes, Vincent
AU - Fryns, Jean Pierre
AU - Ropers, Hans Hilger
AU - Magi, Barbara
AU - Bellan, Cristina
AU - Volpi, Nila
AU - Yntema, Helger G.
AU - Lewis, Sarah E.
AU - Schaffer, Jean E.
AU - Renieri, Alessandra
N1 - Funding Information:
This work was supported by a grant from Telethon (Italy; to A.R.), by INSERM (France) and by the Fondation pour la Recherche Medicale. We are grateful for the clinical support of C. Moraine and C. de Baracé. We also appreciate the contribution of A-D. Ayrault, S. Briault, R. Fulceri and R. Giunti. We thank L. Lozzi for synthetic peptide generation.
PY - 2002/4
Y1 - 2002/4
N2 - X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX)1. For 9 of the 66 MRX entries, the causative gene has been identified1. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene2, 3. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes4-6. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.
AB - X-linked mental retardation (XLMR) is an inherited condition that causes failure to develop cognitive abilities, owing to mutations in a gene on the X chromosome. The latest XLMR update lists up to 136 conditions leading to 'syndromic', or 'specific', mental retardation (MRXS) and 66 entries leading to 'nonspecific' mental retardation (MRX)1. For 9 of the 66 MRX entries, the causative gene has been identified1. Our recent discovery of the contiguous gene deletion syndrome ATS-MR (previously known as Alport syndrome, mental retardation, midface hypoplasia, elliptocytosis, OMIM #300194), characterized by Alport syndrome (ATS) and mental retardation (MR), indicated Xq22.3 as a region containing one mental retardation gene2, 3. Comparing the extent of deletion between individuals with ATS-MR and individuals with ATS alone allowed us to define a critical region for mental retardation of approximately 380 kb, containing four genes4-6. Here we report the identification of two point mutations, one missense and one splice-site change, in the gene FACL4 in two families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines from affected individuals of both families revealed low levels compared with normal cells, indicating that both mutations are null mutations. All carrier females with either point mutations or genomic deletions in FACL4 showed a completely skewed X-inactivation, suggesting that the gene influences survival advantage. FACL4 is the first gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.
UR - http://www.scopus.com/inward/record.url?scp=18544386723&partnerID=8YFLogxK
U2 - 10.1038/ng857
DO - 10.1038/ng857
M3 - Article
C2 - 11889465
AN - SCOPUS:18544386723
VL - 30
SP - 436
EP - 440
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 4
ER -