Submission Details

The IQ MOTIF-CONTAINING PROTEIN B1 (IQCB1) gene is located on chromosome 3 at 3q13.33 and encodes the nephrocystin-5. The IQCB1 gene spans through 15 exons and consists of 65,299 bases. This protein consists of 598 amino acids, with a central coiled-coil region and two calmodulin-binding IQ domains, localized to the primary cilia of renal epithelial cells and connecting cilia of photoreceptor cells. Nephrocystin-5 plays a role in ciliary function, abnormal or loss of function of this protein are associated with retinal degeneration and renal-cyst formation. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism, inheritance pattern, and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: AR Ciliopathy: MONDO:0005308. IQCB1 was first reported in relation to autosomal recessive nephronophthisis and Senior-Loken Syndrome (SLS) in 2005 (Otto et al., PMID: 15723066). Patients with IQCB1 gene mutation are presented with SLS or Leber congenital amaurosis (LCA). SLS typically presents in the first two decades of life as a combination of nephronophthisis (NPHP) and ocular problems. Clinical NPHP consists of polyuria, polydipsia, secondary enuresis, anemia, and chronic kidney disease (CKD) that can progress to kidney failure requiring transplant or dialysis. Patients with SLS can present with severe retinopathy, Leber congenital amaurosis (LCA), or a milder phenotype. LCA is a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction.

The mechanism of pathogenicity is known to be loss of function. At least 544 variants, (deletion, duplication, indel, insertion and single nucleotide variants) have been reported in over 150 probands in over 30 publications (PMIDs: 15723066, 18076122, 25984213, 38522724 included this curation), with the first publication in 2005 and the most recent publication was in 2024. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data and segregation data. This gene-disease relationship is also supported by experimental studies. Takao et al. (PMID: 28736169) report a study on biochemical function of NPHP5, showing that nucleoporin Nup62 and the C termini of the nephronophthisis (NPHP) proteins NPHP4 and NPHP5 interact with the axoneme-associated kinesin-2 motor KIF17 and thus spatially map to the inner region of the ciliary gating zone. They also found that B9D1, AHI1, and the N termini of NPHP4 and NPHP5 interact with the transmembrane protein SSTR3 and thus spatially map to the outer region of the ciliary gating zone. NPHP5 also forms a complex with CEP290 / NPHP6 , and this complex is localized from the basal body to transition zone. B9D1, AHI1, and NPHP5 exhibit little to no turnover at the transition zone and thus define components of a stable gating structure. Being a stable component of the ciliary gating zone, NPHP5 may play a structural role, and NPHP6 may regulate its turnover and/or function during ciliary gating.

Otto el at.( PMID: 15723066) studied expression of the nephrocystin-5 protein, describing that nephrocystin-5 localizes to primary cilia in renal tubular epithelial cells and retinal cells. Studies of an animal model from the same study revealed that nephrocystin-5, (which contain an IQ domain) directly interacts with calmodulin and is complexed with RPGR (retinitis pigmentosa GTPase regulator). Another study from Barbelanne et al.(PMID: 25552655) described that nephrocystin proteins NPHP5 and Cep290 regulate BBSome integrity, ciliary trafficking and cargo delivery. This study revealed that nephrocystin-5 interacts with the BBSome via 2 distinct BBSome-binding sites, which are at the N-terminal region and the C-terminal region. Further mapping studies revealed that the first 157 residues (1–157) and the last 68 residues (530–598) of NPHP5 are critical for binding. Barbelanne et al. (PMID: 25552655) also showed that functional alteration of NPHP5 in non-patient cells was associated with reduced ciliary Smo and BBSome, leading to impaired trafficking to cilia. Rescue experiments in a cell culture model revealed that loss of ciliary BBS2/BBS5 and proximal ciliary staining of BBS2, were largely rescued by full-length NPHP5 (1–598) expression.

Kruczek et al.(PMID: 36084637) presented a study using fibroblasts from a family of patients with LCA/SLS causing from IQCB1 mutations and their unaffected family members as controls. They showed that the patient fibroblasts and RPE demonstrated aberrantly elongated ciliary axonemes. Organoids revealed impaired development of outer segment structures that were modified primary cilia, and mislocalization of visual pigments to photoreceptor cell soma. All patient-derived cells showed reduced levels of CEP290 protein, a critical ciliary transition zone component interacting with NPHP5, providing a plausible mechanism for aberrant ciliary gating and cargo transport. This evidence was classified as a functional alteration in patient cells. Furthermore, they presented evidence from a cell culture model by generating retinal organoids from both control and patient iPSClines. In early-stage retinal organoids(day 70), cilia in patient-derived organoids were significantly longer when compared with equivalent control organoids. Late stage (day 200) patient-derived organoids had significantly increased inner segment/outer segment (IS/OS) thickness, indicating longer photoreceptor cilia. There is also evidence from a non-human model organism (mouse) from Ronquillo et al (PMID: 27328943). The mouse ocular phenotypes was consistent with the human ocular phenotype. *Nphp5-/- *mice develop blindness early in life. Fundi show peripheral and central mottling of the retina. Abnormal quantity and localization of rod and cone proteins are noted in the retina. Nphp5-/- photoreceptor degeneration was complete at 1 mo of age but was delayed significantly in Nphp5-/-;Nrl-/- (cone only) retina. Nphp5-/- mouse embryonic fibroblast developed normal cilia, and *Nphp5-/- *kidney histology at 1 yr of age showed no significant pathology. More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached.

In summary, there is definitive evidence supporting the relationship between IQCB1 and AR Ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has held up over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date August, 28th, 2024 (SOP Version 10).