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: I Longo, S G M Frints, J-P Fryns, I Meloni, C Pescucci, F Ariani, M Borghgraef, M Raynaud, P Marynen, C Schwartz, A Renieri, G Froyen
• Journal: Journal of medical genetics (J Med Genet) Vol. 40 Issue 1 Pg. 11-7 (Jan 2003) ISSN: 1468-6244 [Electronic] England
• PMID: 12525535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Extracts
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Proline
• Coenzyme A Ligases
• FAA2 protein, S cerevisiae
• long-chain-fatty-acid-CoA ligase
• Leucine

Topics

• Adolescent
• Adult
• Amino Acid Substitution (genetics)
• Cell Extracts (chemistry)
• Cell Line
• Child
• Chromosomes, Human, X (genetics)
• Coenzyme A Ligases (blood, genetics)
• Female
• Genetic Carrier Screening (methods)
• Genetic Testing (methods)
• Humans
• Infant
• Leucine (genetics)
• Lymphocytes (chemistry)
• Male
• Mental Retardation, X-Linked (blood, enzymology, etiology, genetics)
• Middle Aged
• Molecular Diagnostic Techniques (methods)
• Mutation, Missense (genetics)
• Pedigree
• Proline (genetics)
• Repressor Proteins
• Saccharomyces cerevisiae Proteins
• Sex Chromosome Aberrations