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FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation

Nature Genetics volume 30, pages 436–440 (2002)Cite this article

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)1. For 9 of the 66 MRX entries, the causative gene has been identified1. 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 gene2,3. 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 genes4,5,6. 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.

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Figure 1: Chromatograms of mutated sequences.
Figure 2: Segregation analysis in the two families and RT-PCR analysis of patient P55.
Figure 3: Schematic representation of FACL4 (upper panel) and comparison of FACS signature motifs (lower panel).
Figure 4: Arachidonyl CoA synthetase activity of affected individuals and controls.
Figure 5: Expression of FACL4 in human cerebellum and hippocampus.

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Acknowledgements

This work was supported by a grant from Telethon (Italy; to A.R.), by INSERM (France) and by the Fondation pour la Recherche Medicale. We are grateful for the clinical support of C. Moraine and C. de Baracé. We also appreciate the contribution of A-D. Ayrault, S. Briault, R. Fulceri and R. Giunti. We thank L. Lozzi for synthetic peptide generation.

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Authors and Affiliations

  1. Department of Molecular Biology, Medical Genetics, University of Siena, Italy

    Ilaria Meloni, Maddalena Muscettola, Ilaria Longo, Mirella Bruttini & Alessandra Renieri

  2. Service de Génétique, Inserm U316, Tours cédex, France

    Martine Raynaud, Marie-Pierre Moizard & Marie Gomot

  3. Inserm U129-ICGM, CHU Cochin, Paris, France

    Jamel Chelly & Vincent des Portes

  4. Genetics Department, University of Leuven, Belgium

    Jean-Pierre Fryns

  5. Max-Planck Institute for Molecular Genetics, Berlin, Germany

    Hans-Hilger Ropers

  6. Department of Molecular of Biology, Biochemistry, University of Siena, Italy

    Barbara Magi

  7. Department of Pathology, University of Siena, Italy

    Cristina Bellan

  8. Department of Biomedical Sciences, University of Siena, Italy

    Nila Volpi

  9. Department of Human Genetics, Nijmegen, The Netherlands

    Helger G. Yntema

  10. Departments of Internal Medicine, Molecular Biology & Pharmacology, Washington University, St. Louis, Missouri, USA

    Sarah E. Lewis & Jean E. Schaffer

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Correspondence to Alessandra Renieri.

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Meloni, I., Muscettola, M., Raynaud, M. et al. FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Nat Genet 30, 436–440 (2002). https://doi.org/10.1038/ng857

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