The KCTD family includes tetramerization (T1) domain containing proteins with diverse biological effects. We identified a novel member of the KCTD family, BTBD10. A comprehensive analysis of protein-protein interactions (PPIs) allowed us to put forth a number of testable hypotheses concerning the biological functions for individual KCTD proteins. In particular, we predict that KCTD20 participates in the AKT-mTOR-p70 S6k signaling cascade, KCTD5 plays a role in cytokinesis in a NEK6 and ch-TOG-dependent manner, KCTD10 regulates the RhoA/RhoB pathway. Developmental regulator KCTD15 represses AP-2α and contributes to energy homeostasis by suppressing early adipogenesis. TNFAIP1-like KCTD proteins may participate in post-replication DNA repair through PCNA ubiquitination. KCTD12 may suppress the proliferation of gastrointestinal cells through interference with GABAb signaling. KCTD9 deserves experimental attention as the only eukaryotic protein with a DNA-like pentapeptide repeat domain. The value of manual curation of PPIs and analysis of existing high-throughput data should not be underestimated.

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher’s exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini–Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3′-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

Nucleotide variants that disrupt normal splicing might be the cause of a large number of diseases. Nevertheless, because of the complexity of splicing regulation, it is not always possible to accurately predict the effect of nucleotide sequence changes on splicing events and mRNA structure. Thereby, a number of newly identified nucleotide variants are falsely classified as VUS (a variant of uncertain significance). In the present study we used the minigene assay to analyze the functional consequences of six intronic (c.142−5T>G, c.142−14C>G, c.142−64A>C, c.141+4A>G, c.1032+ 6T>G, c.682+4delA), one missense (c.140A>G) and one synonymous (c.174C>T) variants in the PAX6 gene found in patients with congenital aniridia. We revealed that all except one (c.142−64A>C) variants lead to the disruption of normal splicing patterns resulting in premature termination codon formation followed by mRNA degradation through the nonsense mediated decay pathway. This produces a null allele of the PAX6 gene. That allowed us to reclassify the analyzed variants as loss-of-function and to establish their functional role.