Senior-Loken syndrome-9 is an autosomal recessive disorder characterized by early-onset nephronophthisis and pigmentary retinopathy. Additional more variable fea...
Senior-Loken syndrome-9 is an autosomal recessive disorder characterized by early-onset nephronophthisis and pigmentary retinopathy. Additional more variable features can include liver defects, skeletal anomalies, and obesity (summary by Bizet et al., 2015).
For a phenotypic description and a discussion of genetic heterogeneity of Senior-Loken syndrome, see 266900.
▼ Clinical Features
Bizet et al. (2015) reported 8 patients from 5 families with nephronophthisis associated with retinal dystrophy, consistent with a diagnosis of Senior-Loken syndrome. The onset of tubulointerstitial nephritis occurred in early childhood, resulting in end-stage renal disease between 3 and 16 years of age. Renal biopsy showed interstitial fibrosis with inflammatory cell infiltrate, atrophic tubules with thickening of the basement membrane, dedifferentiated tubules, and dilated proximal tubules. Retinal dystrophy occurred between 2 months and 20 years, with infrequent occurrences of macular degeneration, nystagmus, and strabismus. Funduscopy showed pigmentary reorganization, papillary pallor, and thin retinal vessels. Four patients had liver defects, including cholestasis and hepatic fibrosis, and 6 had skeletal anomalies, including polydactyly, microdactyly, and small femoral heads. Two patients from 1 family had features reminiscent of Bardet-Biedl syndrome (see, e.g., BBS1; 209900), including developmental delay, obesity, and hypogonadism.
The transmission pattern of SLSN9 in the families reported by Bizet et al. (2015) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In 8 patients from 5 unrelated families with SLNS9, Bizet et al. (2015) identified homozygous or compound heterozygous mutations in the TRAF3IP1 gene (607380.0001-607380.0006). The mutations were found by a combination of linkage analysis and whole-exome sequencing. Expression of the mutations in traf3ip1 morphant zebrafish embryos failed to rescue the ciliopathy phenotype, consistent with the mutations resulting in decreased protein function. Immunohistochemical studies of patient fibroblasts showed absence of IFT54 staining at the transition zone and tips of cilia. Patient cilia were longer than those of controls, but there was no difference in the percentage of ciliated cells, in the localization of key ciliary proteins, or in general ciliary composition. However, patient cilia showed a decrease of adenylyl cyclase III (ADCY3; 600291) and impaired translocation of protein kinase A catalytic subunits from the cilium base to the cytoplasm. Missense mutations were associated with impaired IFT54 localization along cytoplasmic microtubules and with a loss of interaction between IFT54 and MAP4 (157132). Patient kidney tubules and fibroblasts showed increased acetylation of alpha-tubulin that correlated with enhanced MAP4 and increased microtubule stabilization. These defects in microtubule dynamics were associated with loss of apicobasal polarity in epithelialized kidney cells. The findings suggested a role for TRAF3IP1 as a negative regulator of microtubule stability via regulation of MAP4. Bizet et al. (2015) noted that the patient phenotype was milder than that observed in animal models with complete gene disruption, suggesting that the TRAF3IP1 mutations identified in these patients are hypomorphic.
▼ Animal Model
Knockdown of the traf3ip1 homolog 'elipsa' in zebrafish is embryonic lethal and is associated with curved body axis, pronephric cysts, and loss of photoreceptor cells in the retina (Omori et al., 2008; Bizet et al., 2015).
Berbari et al. (2011) found that homozygous loss of the Traf3ip1 gene in mice was embryonic lethal. Mutant mice showed neural developmental defects, cardiac edema, polydactyly, and variable microphthalmia, consistent with ciliary assembly defects. Mutant mice also showed abnormal dorsal-ventral neural tube patterning and diminished expression of a Shh (600725) reporter. Cells derived from mutant mice were unable to form cilia and showed increased cytosolic levels of acetylated microtubules. There was also a marked increase in cell size in culture associated with increased activation of the Mtor (601231) pathway. The findings indicated that Traf3ip1 function is highly conserved in ciliogenesis and is important for proper regulation of a number of essential developmental and cellular pathways.