title: A third MRX family (MRX68) is the result of mutation in the long chain fatty acid-CoA ligase 4 (FACL4) gene: proposal of a rapid enzymatic assay for screening mentally retarded patients.
abstract: BACKGROUND
  The gene encoding fatty acid CoA ligase 4 (FACL4) is mutated in families with non-specific X linked mental retardation (MRX) and is responsible for cognitive impairment in the contiguous gene syndrome ATS-MR (Alport syndrome and mental retardation), mapped to Xq22.3. This finding makes this gene a good candidate for other mental retardation disorders mapping in this region.
  
  
  METHODS
  We have screened the FACL4 gene in eight families, two MRX and six syndromic X linked mental retardation (MRXS), mapping in a large interval encompassing Xq22.3.
  
  
  RESULTS
  We have found a missense mutation in MRX68. The mutation (c.1001C>T in the brain isoform) cosegregates with the disease and changes a highly conserved proline into a leucine (p.P375L) in the first luciferase domain, which markedly reduces the enzymatic activity. Furthermore, all heterozygous females showed completely skewed X inactivation in blood leucocytes, as happens in all reported females with other FACL4 point mutations or deletions.
  
  
  CONCLUSIONS
  Since the FACL4 gene is highly expressed in brain, where it encodes a brain specific isoform, and is located in hippocampal and cerebellar neurones, a role for this gene in cognitive processes can be expected. Here we report the third MRX family with a FACL4 mutation and describe the development of a rapid enzymatic assay on peripheral blood that we propose as a sensitive, robust, and efficient diagnostic tool in mentally retarded males.
authors.affiliation: Medical Genetics, Department of Molecular Biology, University of Siena, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Longo
authors.forename: S G M
authors.initials: SG
authors.lastname: Frints
authors.forename: J-P
authors.initials: JP
authors.lastname: Fryns
authors.forename: I
authors.initials: I
authors.lastname: Meloni
authors.forename: C
authors.initials: C
authors.lastname: Pescucci
authors.forename: F
authors.initials: F
authors.lastname: Ariani
authors.forename: M
authors.initials: M
authors.lastname: Borghgraef
authors.forename: M
authors.initials: M
authors.lastname: Raynaud
authors.forename: P
authors.initials: P
authors.lastname: Marynen
authors.forename: C
authors.initials: C
authors.lastname: Schwartz
authors.forename: A
authors.initials: A
authors.lastname: Renieri
authors.forename: G
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics; D002457:Cell Extracts / Q000737:chemistry; D002460:Cell Line; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D003066:Coenzyme A Ligases / Q000097:blood / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D007223:Infant; D007930:Leucine / Q000235:genetics; D008214:Lymphocytes / Q000737:chemistry; D008297:Male; D038901:X-Linked Intellectual Disability / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques / Q000379:methods; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D011392:Proline / Q000235:genetics; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D012729:Sex Chromosome Aberrations; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D002457:Cell Extracts; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D011392:Proline; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D007930:Leucine