Nature Genetics
30, 436 - 440 (2002)
Published online: 11 March 2002; | doi:10.1038/ng857
FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardationIlaria Meloni1, Maddalena Muscettola1, Martine Raynaud2, Ilaria Longo1, Mirella Bruttini1, Marie-Pierre Moizard2, Marie Gomot2, Jamel Chelly3, Vincent des Portes3, Jean-Pierre Fryns4, Hans-Hilger Ropers5, Barbara Magi6, Cristina Bellan7, Nila Volpi8, Helger G. Yntema9, Sarah E. Lewis10, Jean E. Schaffer10
& Alessandra Renieri11
Medical Genetics, Department of Molecular Biology, University of Siena, Italy. 2
Service de Génétique, Inserm U316, Tours cédex, France. 3
Inserm U129-ICGM, CHU Cochin, Paris, France. 4
Genetics Department, University of Leuven, Belgium. 5
Max-Planck Institute for Molecular Genetics, Berlin, Germany. 6
Biochemistry, Department of Molecular of Biology, University of Siena, Italy. 7
Department of Pathology, University of Siena, Italy. 8
Department of Biomedical Sciences, University of Siena, Italy. 9
Department of Human Genetics, Nijmegen, The Netherlands. 10
Departments of Internal Medicine, Molecular Biology & Pharmacology, Washington University, St. Louis, Missouri, USA.
Correspondence should be addressed to Alessandra Renieri renieri@unisi.itX-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,
5,
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.
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