FACL4, A NEW GENE ENCODING LONG-CHAIN ACYL-COA SYNTHETASE-4, IS DELETED IN A FAMILY WITH ALPORT-SYNDROME, ELLIPTOCYTOSIS, AND MENTAL-RETARDATION

We observed a family in which two boys were diagnosed with Alport synd rome, elliptocytosis, and mental retardation and carried a large delet ion of the Xq22.3-q23 region, encompassing the COL4A5 gene. This sugge sts the possibility of a new contiguous gene syndrome. In an attempt t o characterize the genes contributing to this complex phenotype, we ha ve isolated a gene encoding a new long-chain acyl-CoA synthetase (FACL 4 or LACS4) from the region deleted in these patients. Among several E STs identified by searching the human gene map database maintained at the National Center for Biotechnology Information, using the map posit ion as a query, only one was deleted in the patients. RACE products co ntaining the entire ORF were subsequently generated. Northern blot ana lysis showed a 5-kb mRNA expressed in several tissues except for liver and lung. Brain shows a longer transcript, possibly reflecting the us e of a brain-specific upstream ATG start codon. FACL4 encodes a predic ted protein product of 670 amino acids (711 in brain), with a remarkab le level of conservation compared to the rat acyl-CoA synthetases ACS4 and brain-specific ACS3 protein sequences. We are investigating the p ossibility that the absence of this enzyme may play a role in the deve lopment of mental retardation or other signs associated with Alport sy ndrome in the family. (C) 1998 Academic Press.