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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
  1. I Longo1,
  2. S G M Frints2,
  3. J-P Fryns3,
  4. I Meloni1,
  5. C Pescucci1,
  6. F Ariani1,
  7. M Borghgraef3,
  8. M Raynaud4,
  9. P Marynen2,
  10. C Schwartz5,
  11. A Renieri1,
  12. G Froyen2
  1. 1Medical Genetics, Department of Molecular Biology, University of Siena, Italy
  2. 2Human Genome Laboratory, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
  3. 3Clinical Genetics Unit, University Hospital Leuven, Department of Human Genetics, Leuven, Belgium
  4. 4Service de Génétique, INSERM U316, Tours Cédex, France
  5. 5Greenwood Genetic Center, SC, USA
  1. Correspondence to:
 Dr A Renieri, Medical Genetics, University of Siena, Policlinico Le Scotte, Viale Bracci 2, 53100 Siena, Italy;
 renieri{at}unisi.it

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.

  • non-specific X linked mental retardation
  • FACL4
  • MRX68

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