Disease relevance of OFD1

• The oral-facial-digital syndrome type 1 (OFD1), a cause of polycystic kidney disease and associated malformations, maps to Xp22.2-Xp22.3 [1].
• MSL3L1 was identified by database queries with genomic sequence from BAC GS-590J6 (GenBank AC0004554) in Xp22.3 and was evaluated as a candidate gene for several developmental disorders mapping to this region, including OFD1 and SED tarda, as well as Aicardi syndrome and Goltz syndrome [2].
• We detected multiple pancreatic cysts in one member affected by OFD1 although there were no symptoms of pancreatic disease; this constitutes a novel radiological feature of the syndrome [3].
• Comparing the phenotype of the families with a pathogenic mutation to families with absence of OFD1 mutation, polycystic kidneys and short stature were significantly more frequent in the group with no OFD1 mutation, whereas lingual hamartomas were significantly more frequent in the group with OFD1 mutation [4].
• OFD1 is the gene responsible for the oral-facial-digital syndrome type 1, a cause of inherited cystic renal disease [5].

Psychiatry related information on OFD1

• The involvement of OFD1 in oral-facial-digital type I syndrome demonstrates an important role of this gene in human development [6].
• We report on a large family in which a novel X-linked recessive mental retardation (XLMR) syndrome comprising macrocephaly and ciliary dysfunction co-segregates with a frameshift mutation in the OFD1 gene [7].

High impact information on OFD1

• The oral-facial-digital type I (OFD1) syndrome (OMIM 311200) is a human developmental disorder; affected individuals have craniofacial and digital abnormalities and, in 15% of cases, polycystic kidney [8].
• Using a Cre-loxP system, we generated knockout animals lacking Ofd1 and reproduced the main features of the disease, albeit with increased severity, possibly owing to differences of X inactivation patterns between human and mouse [8].
• These including focal dermal hypoplasia, oral-facial-digital syndrome type I (ref. 3) and epilepsy with bilateral periventricular heterotopias [9].
• There was a maximum lod score of 3.32 in an 'affecteds only' analysis using a marker within the KAL gene (theta = 0.0 ), thereby confirming the location of the gene for OFD1 on the X chromosome [1].
• Therefore, the OFD1 gene product appears to have widespread importance in organogenesis and is essential for fetal survival [1].

Biological context of OFD1

• Furthermore, this mapping study suggests a possible mouse model for OFD1 as the X-linked dominant Xpl mutant, in which polydactyly and renal cystic disease occurs, maps to the homologous region of the mouse X chromosome [1].
• In two OFD1 kindreds affected by PKD, a frameshift mutation and a splice-site mutation were detected [10].
• This study used a combination of microscopic, biochemical, and overexpression approaches to demonstrate that OFD1 protein is a core component of the human centrosome throughout the cell cycle [5].
• The first deletion, the largest known to affect OFD1, was revealed by identifying four novel transcripts that all lacked exons 7-9 [11].
• CONCLUSIONS: This kindred illustrates the inheritance pattern of OFD1 and its accompanying PKD [3].

Anatomical context of OFD1

• These striking patterns of OFD1 localization within cells place the protein at key sites, where it may play roles not only in microtubule organization (centrosomal function) but also in mechanosensation of urine flow (a primary ciliary function) [5].
• Moreover, using normal human renal mesenchymal cell lines, the immunoreactive protein colocalized with gamma-tubulin, suggesting that OFD1 is associated with the centrosome [10].
• Oral-facial-digital type 1 (OFD1) syndrome is an X-linked dominant condition characterized by malformations of the face, oral cavity, and digits [12].
• We report on 2 families in which OFD syndrome type 1 was observed with central nervous system (CNS) malformations and 3 sporadic cases of OFD with CNS defects, most likely representing fresh mutations for OFD 1 [13].
• Only recently have intraocular findings been described in oral-facial-digital syndrome (OFDS), including 5 cases of chorioretinal colobomas and 1 case of optic nerve coloboma [14].

Associations of OFD1 with chemical compounds

• By immunoprobing human metanephroi and kidney epithelial lines, it was found that, during acquisition of epithelial polarity, OFD1 became localized to the apical zone of nephron precursor cells and then to basal bodies at the origin of primary cilia in fully differentiated epithelia [5].

Other interactions of OFD1

• Twenty-four new localizations have been established, including five in previously reported conditions (FG, Carpenter, Arts, OPA2, and OFD1) [15].
• Mutations in OFD1 modified its localization to the Golgi apparatus and in some cases also to the nucleus [16].
• By virtue of its mapping assignment to the Xp22 region, Cxorf5 represents a candidate gene for at least four human diseases, namely spondyloepiphiseal dysplasia late, oral-facial-digital syndrome type 1, craniofrontonasal syndrome, and a nonsyndromic sensorineural deafness [17].
• The combination of malformations observed overlaps with that of the oral-facial-digital syndrome, hydrolethalus syndrome, and Pallister-Hall syndrome [18].
• This case illustrates ongoing problems in differentiating hydrolethalus, both pre- and postnatally, from other midline malformation syndromes including Pallister-Hall, Smith-Lemli-Opitz, pseudo-trisomy 13, oral facial-digital syndrome, and Meckel syndrome [19].

Analytical, diagnostic and therapeutic context of OFD1

• Northern blot detected OFD1 mRNA in metanephros, brain, tongue, and limb, all organs affected in the syndrome [10].
• Comparative sequence analysis demonstrated that OFD1 is conserved among vertebrates and absent in invertebrates [12].
• A cystic renal lesion is described in a girl with oral-facial-digital syndrome, type I. Excretory urography was normal at 1 yr of age; however, flank masses, hypertension, and renal failure were discovered at 11 yr of age [20].
• Prenatal diagnosis of oral-facial-digital syndrome, type I [21].

References