ORIGINAL ARTICLE

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

I Longo¹, S G M Frints², J-P Fryns³, I Meloni¹, C Pescucci¹, F Ariani¹, M Borghgraef³, M Raynaud⁴, P Marynen², C Schwartz⁵, A Renieri¹, G Froyen²

¹ Medical Genetics, Department of Molecular Biology, University of Siena, Italy
² Human Genome Laboratory, Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium
³ Clinical Genetics Unit, University Hospital Leuven, Department of Human Genetics, Leuven, Belgium
⁴ Service de Génétique, INSERM U316, Tours Cédex, France
⁵ Greenwood Genetic Center, SC, USA

Correspondence to:
Correspondence to:
Dr A Renieri, Medical Genetics, University of Siena, Policlinico Le Scotte, Viale Bracci 2, 53100 Siena, Italy;
renieri{at}unisi.it

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.

Keywords: non-specific X linked mental retardation; FACL4; MRX68

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