OFD1, the Gene Mutated in Oral-Facial-Digital Syndrome Type 1, Is Expressed in the Metanephros and in Human Embryonic Renal Mesenchymal Cells

Abstract

Abstract. Oral-facial-digital syndrome type 1 (OFD1) causes polycystic kidney disease (PKD) and malformations of the mouth, face and digits. Recently, a gene on Xp22, OFD1, was reported to be mutated in a limited set of OFD1 patients. This study describes mutation analysis in six further OFD1 families. Additionally, gene expression was sought in human development. In two OFD1 kindreds affected by PKD, a frameshift mutation and a splice-site mutation were detected. In four apparently sporadic cases, three frameshift and a missense mutation were found. Using RT-PCR of RNA from firsttrimester normal human embryos, both alternative splice forms of mRNA (OFD1a and OFD1b) were found to be widely expressed in organogenesis. Northern blot detected OFD1 mRNA in metanephros, brain, tongue, and limb, all organs affected in the syndrome. A polyclonal antibody directed to a C-terminal OFD1a epitope detected a 120-kD protein in the metanephros and in human renal mesenchymal cell lines. In normal human embryos, OFD1a immunolocalized to the metanephric mesenchyme, oral mucosa, nasal and cranial cartilage, and brain. Moreover, using normal human renal mesenchymal cell lines, the immunoreactive protein colocalized with ␥-tubulin, suggesting that OFD1 is associated with the centrosome. First, it is concluded that OFD1 mutations would generally be predicted to result in unstable transcripts or nonfunctional proteins. Second, OFD1 is expressed in human organogenesis; on the basis of the metanephric expression pattern, the results suggest that OFD1 plays a role in differentiation of metanephric precursor cells.

Branching morphogenesis and kidney disease

“…In humans, cilia gene mutations disrupt regulation of tubule epithelial cell proliferation, thereby resulting in cyst formation. Mutation of PKD1 and PKD2, genes that code for ciliary structural proteins, underlie most forms of ADPKD, whereas mutations in OFD1, a gene involved in cilia generation and structure, and are associated with X-linked dominant polycystic kidney disease (Romio et al, 2003). These studies underscore the importance of cilia function in the regulation of tubule lumen diameter.…”

Mechanosensory-defective, male-sterileuncmutants identify a novel basal body protein required for ciliogenesis inDrosophila

“…UNC shares a conserved, partial lissencephaly homology (LisH) motif with a number of proteins involved in microtubule organization (Emes and Ponting, 2001), but the specific function of this motif is unknown. In humans, the gene mutated in oral-facial-digital syndrome (OFD1), a probable ciliary disorder, encodes a protein with a similar arrangement of a LisH domain and coiled-coil segments, which is localized to centrosomes (Ferrante et al, 2001;Romio et al, 2003). OFD1 may therefore have a basal body function similar to that of UNC.…”

Genomic deletions ofOFD1account for 23% of oral-facial-digital type 1 syndrome after negative DNA sequencing

“…OFD1 is also implicated in a novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction (Budny et al, 2006). In OFDI syndrome, 92 mutations (frameshift, nonsense, missense and splice mutations) have been identified by DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene (Ferrante et al, 2001;Rakkolainen et al, 2002;Romio et al, 2003;Thauvin-Robinet et al, 2006; Prattichizzo et al, in press).…”

“…OFD1 is also implicated in a novel X-linked recessive mental retardation syndrome comprising macrocephaly and ciliary dysfunction (Budny et al, 2006). In OFDI syndrome, 92 mutations (frameshift, nonsense, missense and splice mutations) have been identified by DNA bi-directional sequencing of the exons and intron-exon boundaries of the OFD1 gene (Ferrante et al, 2001;Rakkolainen et al, 2002;Romio et al, 2003;Thauvin-Robinet et al, 2006; Prattichizzo et al, in press).To date, no mutation of the OFD1 gene has been detected in about 20% of patients presenting with clinical signs +/-a familial history consistent with OFD1 syndrome (Ferrante et al, 2001;Thauvin-Robinet et al, 2006; Prattichizzo et al, in press). A subset of these cases can be explained by genetic heterogeneity or may be phenocopies.…”