title: FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation.
abstract: 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). For 9 of the 66 MRX entries, the causative gene has been identified. 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 gene. 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 genes. 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.
authors.affiliation: Medical Genetics, Department of Molecular Biology, University of Siena, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Meloni
authors.forename: Maddalena
authors.initials: M
authors.lastname: Muscettola
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Mirella
authors.initials: M
authors.lastname: Bruttini
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Moizard
authors.forename: Marie
authors.initials: M
authors.lastname: Gomot
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Vincent
authors.initials: V
authors.lastname: des Portes
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.forename: Barbara
authors.initials: B
authors.lastname: Magi
authors.forename: Cristina
authors.initials: C
authors.lastname: Bellan
authors.forename: Nila
authors.initials: N
authors.lastname: Volpi
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lewis
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D002531:Cerebellum / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003066:Coenzyme A Ligases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D005091:Exons; D005192:Family Health; D005260:Female; D008040:Genetic Linkage; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins; D012689:Sequence Homology, Nucleic Acid; D014960:X Chromosome; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D003066:Coenzyme A Ligases; C033896:arachidonate - CoA ligase; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase