A novel missense pathogenic variants of TMEM53 in an Iranian family with craniotubular dysplasia, Ikegawa type
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Mechanisms of NLRP3 activation and inhibition elucidated by functional analysis of disease-associated variants
The NLRP3 inflammasome is a multiprotein complex that mediates caspase-1 activation and the release of proinflammatory cytokines, including interleukin (IL)-1β and IL-18. Gain-of-function variants in the gene encoding NLRP3 (also called cryopyrin) lead to constitutive inflammasome activation and excessive IL-1β production in cryopyrin-associated periodic syndromes (CAPS). Here we present functional screening and automated analysis of 534 NLRP3 variants from the international INFEVERS registry and the ClinVar database. This resource captures the effect of NLRP3 variants on ASC speck formation spontaneously, at low temperature, after inflammasome stimulation and with the specific NLRP3 inhibitor MCC950. Most notably, our analysis facilitated the updated classification of NLRP3 variants in INFEVERS. Structural analysis suggested multiple mechanisms by which CAPS variants activate NLRP3, including enhanced ATP binding, stabilizing the active NLRP3 conformation, destabilizing the inactive NLRP3 complex and promoting oligomerization of the pyrin domain. Furthermore, we identified pathogenic variants that can hypersensitize the activation of NLRP3 in response to nigericin and cold temperature exposure. We also found that most CAPS-related NLRP3 variants can be inhibited by MCC950; however, NLRP3 variants with changes to proline affecting helices near the inhibitor binding site are resistant to MCC950, as are variants in the pyrin domain, which likely trigger activation directly with the pyrin domain of ASC. Our findings could help stratify the CAPS population for NLRP3 inhibitor clinical trials and our automated methodologies can be implemented for molecules with a different mechanism of activation and in laboratories worldwide that are interested in adding new functionally validated NLRP3 variants to the resource. Overall, our study provides improved diagnosis for patients with CAPS, mechanistic insight into the activation of NLRP3 and stratification of patients for the future application of targeted therapeutics.
Genotype of PAX2-related disorders correlates with kidney and ocular manifestations
PAX2-related disorders encompass renal coloboma syndrome (RCS) and hereditary focal segmental glomerulosclerosis (FSGS) type 7. We retrospectively analyzed 27 Korean patients with PAX2 pathogenic variants detected between 2004 and 2022 and conducted a literature review of 328 cases, including 301 previously reported. In our cohort, 19 had RCS, 4 had FSGS, and 4 had isolated congenital anomalies of the kidneys and urinary tract. Patients were classified by variant type into predicted loss of function (pLoF) and non-pLoF variant groups, and by variant location into paired domain and other sites group. pLoF variants were predominantly associated with RCS, observed in 82% of patients in both our data (18 of 22, P = 0.017) and the literature (140 of 171, P < 0.001). Kidney failure developed in 52% of Korean patients at a median age of 14.5 years, with no difference in kidney survival between variant types. However, the literature review indicated faster progression to kidney failure in patients with pLoF variants (11.0 vs. 24.0 years; pLoF, n = 138 vs. non-pLoF, n = 71; P = 0.002), with no significant difference by variant location. Ocular manifestations were more common, had earlier onset, and were more severe in the pLoF variants group in our cohort (P = 0.038). The literature confirmed a higher prevalence of ocular involvement in patients with pLoF variants (pLoF, n = 175 vs. non-pLoF, n = 88; P < 0.001) and in those with paired domain variants (P = 0.01). pLoF variants in PAX2 were associated with worse kidney and ocular outcomes. These findings support genotype-phenotype correlations, contributing to tailored management in patients with PAX2-related disorders.
Selection for somatic escape variants in SERPINA1 in the liver of patients with alpha-1 antitrypsin deficiency
Somatic variants accumulate in non-malignant tissues with age. Functional variants, leading to clonal advantage of hepatocytes, accumulate in the liver of patients with acquired chronic liver disease (CLD). Whether somatic variants are common to CLD from differing etiologies is unknown. We analyzed liver somatic variants in patients with genetic CLD from alpha-1 antitrypsin (A1AT) deficiency or hemochromatosis. We show that somatic variants in SERPINA1, the gene encoding A1AT, are strongly selected for in A1AT deficiency, with evidence of convergent evolution. Acquired SERPINA1 variants are clustered at the carboxyl terminus of A1AT, leading to truncation. In vitro and in vivo, C-terminal truncation variants reduce disease-associated Z-A1AT polymer accumulation and disruption of the endoplasmic reticulum, supporting the C-terminal domain swap mechanism. Therefore, somatic escape variants from a deleterious germline variant are selected for in A1AT deficiency, suggesting that functional somatic variants are disease-specific in CLD and point to disease-associated mechanisms.
The WAVE complex in developmental and adulthood brain disorders
Actin polymerization and depolymerization are fundamental cellular processes required not only for the embryonic and postnatal development of the brain but also for the maintenance of neuronal plasticity and survival in the adult and aging brain. The orchestrated organization of actin filaments is controlled by various actin regulatory proteins. Wiskott‒Aldrich syndrome protein-family verprolin-homologous protein (WAVE) members are key activators of ARP2/3 complex-mediated actin polymerization. WAVE proteins exist as heteropentameric complexes together with regulatory proteins, including CYFIP, NCKAP, ABI and BRK1. The activity of the WAVE complex is tightly regulated by extracellular cues and intracellular signaling to execute its roles in specific intracellular events in brain cells. Notably, dysregulation of the WAVE complex and WAVE complex-mediated cellular processes confers vulnerability to a variety of brain disorders. De novo mutations in WAVE genes and other components of the WAVE complex have been identified in patients with developmental disorders such as intellectual disability, epileptic seizures, schizophrenia, and/or autism spectrum disorder. In addition, alterations in the WAVE complex are implicated in the pathophysiology of Alzheimer’s disease and Parkinson’s disease, as well as in behavioral adaptations to psychostimulants or maladaptive feeding.
Whole-genome sequencing analysis identifies rare, large-effect noncoding variants and regulatory regions associated with circulating protein levels
The contribution of rare noncoding genetic variation to common phenotypes is largely unknown, as a result of a historical lack of population-scale whole-genome sequencing data and the difficulty of categorizing noncoding variants into functionally similar groups. To begin addressing these challenges, we performed a cis association analysis using whole-genome sequencing data, consisting of 1.1 billion variants, 123 million noncoding aggregate-based tests and 2,907 circulating protein levels in ~50,000 UK Biobank participants. We identified 604 independent rare noncoding single-variant associations with circulating protein levels. Unlike protein-coding variation, rare noncoding genetic variation was almost as likely to increase or decrease protein levels. Rare noncoding aggregate testing identified 357 conditionally independent associated regions. Of these, 74 (21%) were not detectable by single-variant testing alone. Our findings have important implications for the identification, and role, of rare noncoding genetic variation associated with common human phenotypes, including the importance of testing aggregates of noncoding variants.
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