The CUL3 gene is located on chromosome 2 at q36.2 and encodes cullin-3, a scaffolding component of the Cullin-RING ligase (CRL) complex that belongs to a class of E3 ubiquitin ligases that mediate polyubiquitination of specific target proteins destined for degradation. E3 ligases containing CUL3 interact with KLHL3 and are involved in controlling blood pressure in the body by regulating the amount of WNK1 and WNK4 available. CUL3 mutation was first reported in relation to autosomal dominant Pseudohypoaldosteronism, type II (PHA2E) in 2012 (Boyden et al., PMID: 22266938). This disorder is also known as Gordon syndrome, and familial hyperkalemic hypertension. The preferred disease name suggested for this disorder is ‘Familial hypertension with hyperkalaemia - CUL3’. The disorder is characterized by hyperkalemia, hypertension, metabolic acidosis and suppressed plasma renin levels despite a normal glomerular filtration rate. CUL3 mutation has also been associated with autosomal dominant Neurodevelopmental disorder with or without autism or seizures. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, although both conditions have an AD inheritance, there is a difference in molecular mechanism and in clinical phenotype. Therefore, the following disease entities have been split into two distinct disease entities: Pseudohypoaldosteronism, type IIE (OMIM:614496) and Neurodevelopmental disorder with or without autism or seizures (OMIM:619239). Autosomal dominant Neurodevelopmental disorder with or without autism or seizures has been curated separately by the ID/Austim GCEP on 1/16/2021. Nine variants (intronic, canonical splice, splice donor, splice acceptor, splice enhancer) that have been reported in 8 probands in 4 publications (PMIDs: 22266938, 24266877, 29511623, 34480842) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease association is also supported by expression studies, protein interaction studies, and mouse models. (PMIDs: 29869755, 26286618). In summary, CUL3 is definitively associated with autosomal dominant familial hypertension with hyperkalaemia - CUL3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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