Nephronophthisis 12
A number sign (#) is used with this entry because nephronophthisis-12 (NPHP12) is caused by homozygous or compound heterozygous mutation in the TTC21B gene (612014) on chromosome 2q24. Heterozygous mutation in the TTC21B gene has been found in patients with Joubert syndrome-11 (JBTS11), a related cilopathy.
For a general phenotypic description and a discussion of genetic heterogeneity of NPHP, see 256100.
For a general phenotypic description and a discussion of genetic heterogeneity of Joubert syndrome, see 213300.
Molecular GeneticsIn affected members of 2 unrelated consanguineous families with nephronophthisis-12, Davis et al. (2011) identified a homozygous mutation in the TTC21B gene (P209L; 612014.0001). One family was of Portuguese and the other of Egyptian descent. In vitro and in vivo functional expression studies in mammalian cells and zebrafish indicated that the mutant protein was a hypomorphic allele. In 2 additional families with early-onset NPHP with extrarenal manifestations, the P209L allele was found in compound heterozygosity with another pathogenic TTC21B allele: C552X (612014.0002) and a splice site mutation (612014.0003), respectively. Both of the latter mutations were shown by expression studies to be functionally null alleles. Haplotype analysis indicated a founder effect for the P209L allele. In addition, heterozygous functionally pathogenic alleles were found in about 5% of the total cohort, including 3 unrelated patients with Joubert syndrome-11 (JBTS11) suggesting that TTC21B might be a common contributor to the total mutational load in ciliopathies. No clinical details on the patients were provided.