Identification and characterization of KLHL4, a novel human homologue of the Drosophila Kelch gene that maps within the X-linked cleft palate and ankyloglossia (CPX) critical region

X-linked cleft palate (CPX) is a rare nonsyndromic form of orofacial clefti ng that is, unlike more common forms, inherited as a highly penetrant Mende lian trait, Linkage studies using a large Icelandic kindred localized the g ene to Xq21.3, and a physical map defining a 2.0-Mb candidate region was su bsequently constructed. Genomic sequence is now available for much of the c ritical region and has been surveyed for potential transcriptional units. T hrough this analysis, we have identified a novel human homologue of Kelch, KLHL4. The transcript represents a mRNA of similar to3.6 kb and encodes a p rotein of 718 amino acids. Protein domain analysis reveals six tandem repea ts (Kelch repeats) at the C-terminus and a POZ/BTB protein-binding domain t oward the N-terminus, characteristic of Drosophila Kelch and other family m embers. KLHL4 consists of 11 exons spanning a genomic interval of similar t o 150 kb, From EST sequences and RT-PCR analysis, there is evidence for the use of alternative 3' UTRs, The mRNA is expressed in a range of fetal tiss ues including tongue, palate, and mandible, Mutational analysis in affected CPX patients revealed one sequence alteration that was most likely to be a silent polymorphism. (C) 2001 Academic Press.