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Alternative titles; symbols
ACYL-CoA SYNTHETASE 4; ACS4
Gene map locus Xq22.3TEXT
DESCRIPTION
Long chain acyl-CoA synthetase (LACS), or long chain fatty acid-CoA ligase (FACL; EC 6.2.1.3), converts free long chain fatty acids into fatty acyl-CoA esters, which are key intermediates in the synthesis of complex lipids. See FACL2 (152425). The FACL4 gene encodes a form of LACS and is expressed in several tissues, including brain. 
CLONING
Kang et al. (1997) identified a rat acyl-CoA synthetase, called ACS4 by them, that preferentially uses arachidonate and eicosapentaenoate as substrates. By carrying out a BLAST search with rat ACS4 amino acid sequence as query, Cao et al. (1998) identified ESTs encoding human FACL4. They used the ESTs to identify a brain cDNA containing the remainder of the FACL4 coding region. The FACL4 cDNA encoded an active FACL that showed preference for arachidonic acid as a substrate when expressed in mammalian cells. The sequence of the predicted 670-amino acid human protein is 97% identical to that of rat ACS4.
Independently, Piccini et al. (1998) cloned FACL4 cDNAs. Northern blot analysis revealed that FACL4 was expressed as a 5-kb mRNA in a variety of tissues. The transcript in brain appeared to be slightly larger. Sequence analysis of FACL4 cDNAs showed that the larger mRNAs resulted from alternative splicing and encoded a predicted protein with an additional 41 N-terminal amino acids. The authors stated that the 41-amino acid peptide is hydrophobic and may change the intracellular localization of FACL4 or its fatty acid specificity.
Vitelli et al. (2000) cloned the mouse Facl4 and Ammecr1 (300195) genes.
Meloni et al. (2002) found that FACL4 is highly expressed in adult human brain, especially in the cerebellum and hippocampus, showing a distribution very similar to that obtained in mouse. A strong cytoplasmic staining was found in the Purkinje and granular cells of the cerebellum and the pyramidal layer of hippocampus, indicating that FACL4 is specifically expressed in neurons and not in glial cells. Within the neuron, FACL4 is found primarily in neuronal soma and proximal dendrites.
GENE STRUCTURE
Minekura et al. (2001) determined that the FACL4 gene contains 16 exons and spans approximately 90 kb. The 5-prime flanking region does not have a typical TATA box but has a CCAAT box as well as transcription factor binding sites for AP2 (see 107580), AP4 (600743), and CREB (123810). Minekura et al. (2001) identified several other potential binding sites.
MAPPING
By analysis of a somatic cell hybrid panel and by fluorescence in situ hybridization, Cao et al. (1998) mapped the FACL4 gene to Xq23. Piccini et al. (1998) further refined the map position to Xq22.3 by showing that the FACL4 gene was contained within a YAC contig from that region. Vitelli et al. (2000) mapped the mouse Facl4 and Ammecr1 genes to chromosome XF1-F3 by FISH.
MOLECULAR GENETICS
Piccini et al. (1998) reported that the 2 patients with Alport syndrome, elliptocytosis, and mental retardation described by Jonsson et al. (1998)(300194) carried a large deletion of the COL4A5 (303630) region that included the contiguous FACL4. Piccini et al. (1998) suggested that the absence of FACL4 might play a role in the development of mental retardation or other signs associated with Alport syndrome in these patients.
Meloni et al. (2002) reported the identification of 2 point mutations, 1 missense and 1 splice site change, in the FACL4 gene in 2 families with nonspecific mental retardation. Analysis of enzymatic activity in lymphoblastoid cell lines of 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.
ANIMAL MODEL
Cho et al. (2001) found that female mice heterozygous for Facl4 deficiency became pregnant less frequently and produced small litters, with 40% of embryos surviving gestation. The transmission rate for the disrupted allele was low. Heterozygous females had extremely enlarged uteri and lumina filled with numerous proliferative cysts, and showed marked uterine accumulation of prostaglandins. Hemizygous males (-/Y) appeared normal and were fertile when crossed with wildtype females.
.0001 MENTAL RETARDATION, X-LINKED 63 [FACL4, ARG529SER]
In a family segregating nonsyndromic X-linked mental retardation (MRX63; 300387), Meloni et al. (2002) identified a C-to-A transversion at nucleotide 1585 in exon 15 of the FACL4 gene, leading to an arg-to-ser substitution in amino acid 529 (R529S), corresponding to amino acid 570 of the brain isoform (R570S). All females carrying this mutation had completely skewed X inactivation in leukocytes.
.0002 MENTAL RETARDATION, X-LINKED 63 [FACL4, IVS10, A-G, -2 ]
In a patient with severe nonspecific X-linked mental retardation (MRX63; 300387), Meloni et al. (2002) identified an A-to-G transition at the -2 position of the splice site of intron 10 of the FACL4 gene (1003-2A-G), resulting in activation of a cryptic splice site within the intron and inducing an additional 28 nucleotides with an in-frame stop codon. This mutation was not identified in 600 normal control chromosomes. The carrier mother of the affected male had completely skewed X inactivation in leukocytes.
.0003 MENTAL RETARDATION, X-LINKED 68 [FACL4, PRO375LEU ]
In affected members of a family with nonspecific X-linked mental retardation (MRX68; 300387), Longo et al. (2003) identified a 1001C-T change in the FACL4 gene, resulting in a pro375-to-leu (P375L) substitution. Carrier females had 100% skewed X inactivation. Functional studies of the mutant protein showed a marked reduction in enzyme activity. The authors suggested that reduction of FACL4 activity may lead to deranged fatty acid metabolism in neurons, causing defects of neuron outgrowth, synaptogenesis, and other developmental functions important for normal brain development.
REFERENCES
- 1. Cao, Y.; Traer, E.; Zimmerman, G. A.; McIntyre, T. M.; Prescott, S. M. :
- Cloning, expression, and chromosomal localization of human long-chain fatty acid-CoA ligase 4 (FACL4). Genomics 49: 327-330, 1998.
PubMed ID : 9598324
- 2. Cho, Y.-Y.; Kang, M.-J.; Sone, H.; Suzuki, T.; Abe, M.; Igarashi, M.; Tokunaga, T.; Ogawa, S.; Takei, Y. A.; Miyazawa, T.; Sasano, H.; Fujino, T.; Yamamoto, T. T. :
- Abnormal uterus with polycysts, accumulation of uterine prostaglandins, and reduced fertility in mice heterozygous for acyl-CoA synthetase 4 deficiency. Biochem. Biophys. Res. Commun. 284: 993-997, 2001.
PubMed ID : 11409893
- 3. Jonsson, J. J.; Renieri, A.; Gallagher, P. G.; Kashtan, C. E.; Cherniske, E. M.; Bruttini, M.; Piccini, M.; Vitelli, F.; Ballabio, A.; Pober, B. R. :
- Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis: a new X linked contiguous gene deletion syndrome? J. Med. Genet. 35: 273-278, 1998.
PubMed ID : 9598718
- 4. Kang, M. J.; Fujino, T.; Sasano, H.; Minekura, H.; Yabuki, N.; Nagura, H.; Iijima, H.; Yamamoto, T. T. :
- A novel arachidonate-preferring acyl-CoA synthetase is present in steroidogenic cells of the rat adrenal, ovary, and testis. Proc. Nat. Acad. Sci. 94: 2880-2884, 1997.
PubMed ID : 9096315
- 5. Longo, I.; Frints, S. G. M.; Fryns, J.-P.; Meloni, I.; Pescucci, C.; Ariani, F.; Borghgraef, M.; Raynaud, M.; Marynen, P.; Schwartz, C.; Renieri, A.; Froyen, G. :
- 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. J. Med. Genet. 40: 11-17, 2003.
PubMed ID : 12525535
- 6. Meloni, I.; Muscettola, M.; Raynaud, M.; Longo, I.; Bruttini, M.; Moizard, M.-P.; Gomot, M.; Chelly, J.; des Portes, V.; Fryns, J.-P.; Ropers, H.-H.; Magi, B.; Bellan, C.; Volpi, N.; Yntema, H. G.; Lewis, S. E.; Schaffer, J. E.; Renieri, A. :
- FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation. Nature Genet. 30: 436-440, 2002.
PubMed ID : 11889465
- 7. Minekura, H.; Kang, M.-J.; Inagaki, Y.; Cho, Y.-Y.; Suzuki, H.; Fujino, T.; Yamamoto, T. T. :
- Exon/intron organization and transcription units of the human acyl-CoA synthetase 4 gene. Biochem. Biophys. Res. Commun. 286: 80-86, 2001.
PubMed ID : 11485311
- 8. Piccini, M.; Vitelli, F.; Bruttini, M.; Pober, B. R.; Jonsson, J. J.; Villanova, M.; Zollo, M.; Borsani, G.; Ballabio, A.; Renieri, A. :
- FACL4, a new gene encoding long-chain acyl-CoA synthetase 4, is deleted in a family with Alport syndrome, elliptocytosis, and mental retardation. Genomics 47: 350-358, 1998.
PubMed ID : 9480748
- 9. Vitelli, F.; Meloni, I.; Fineschi, S.; Favara, F.; Tiziana Storlazzi, C.; Rocchi, M.; Renieri, A. :
- Identification and characterization of mouse orthologs of the AMMECR1 and FACL4 genes deleted in AMME syndrome: orthology of Xq22.3 and MmuXF1-F3. Cytogenet. Cell Genet. 88: 259-263, 2000.
PubMed ID : 10828604
CONTRIBUTORS
Cassandra L. Kniffin - updated : 12/8/2003
Patricia A. Hartz - updated : 6/13/2002
Ada Hamosh - updated : 3/29/2002
Carol A. Bocchini - updated : 2/15/2001
CREATION DATE
Rebekah S. Rasooly : 11/5/1998
EDIT HISTORY
mgross : 1/6/2004
carol : 12/12/2003
ckniffin : 12/8/2003
carol : 4/18/2003
carol : 6/19/2002
terry : 6/13/2002
alopez : 4/2/2002
terry : 3/29/2002
mgross : 2/22/2001
mcapotos : 2/16/2001
carol : 2/15/2001
terry : 4/25/2000
carol : 6/1/1999
alopez : 11/5/1998
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