CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy

Osawa, Madori; Ogura, Yuichiro; Isobe, Kiyoshi; Uchida, Shinichi; Nonoyama, Shigeaki; Kawaguchi, Hiroyuki

doi:10.1007/s00467-013-2496-6

Cited by 25 publications

(23 citation statements)

References 6 publications

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“…Interestingly, although FHHt patients with mutations in CUL3, KLHL3 or WNK present the same clinical symptoms, those with mutations in CUL3 have a more severe phenotype, evident in terms of both an earlier age-of-onset and the degree of hypertension and electrolyte disturbance reported [15, 84, 85]. So far, all the reported FHHt CUL3 mutations show the deletion of exon 9 in the CUL3 mRNA which results in the loss of amino acid residues 403–459 in the protein.…”

Section: Cul3–klhl3 As Upstream Regulators Of Wnk Kinasesmentioning

confidence: 99%

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WNK signalling pathways in blood pressure regulation

Murthy

Kurz

O’Shaughnessy

2016

Cell. Mol. Life Sci.

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Hypertension (high blood pressure) is a major public health problem affecting more than a billion people worldwide with complications, including stroke, heart failure and kidney failure. The regulation of blood pressure is multifactorial reflecting genetic susceptibility, in utero environment and external factors such as obesity and salt intake. In keeping with Arthur Guyton's hypothesis, the kidney plays a key role in blood pressure control and data from clinical studies; physiology and genetics have shown that hypertension is driven a failure of the kidney to excrete excess salt at normal levels of blood pressure. There is a number of rare Mendelian blood pressure syndromes, which have shed light on the molecular mechanisms involved in dysregulated ion transport in the distal kidney. One in particular is Familial hyperkalemic hypertension (FHHt), an autosomal dominant monogenic form of hypertension characterised by high blood pressure, hyperkalemia, hyperchloremic metabolic acidosis, and hypercalciuria. The clinical signs of FHHt are treated by low doses of thiazide diuretic, and it mirrors Gitelman syndrome which features the inverse phenotype of hypotension, hypokalemic metabolic alkalosis, and hypocalciuria. Gitelman syndrome is caused by loss of function mutations in the thiazide-sensitive Na/Cl cotransporter (NCC); however, FHHt patients do not have mutations in the SCL12A3 locus encoding NCC. Instead, mutations have been identified in genes that have revealed a key signalling pathway that regulates NCC and several other key transporters and ion channels in the kidney that are critical for BP regulation. This is the WNK kinase signalling pathway that is the subject of this review.

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Section: Cul3–klhl3 As Upstream Regulators Of Wnk Kinasesmentioning

confidence: 99%

“…So far, all the reported FHHt CUL3 mutations show the deletion of exon 9 in the CUL3 mRNA which results in the loss of amino acid residues 403–459 in the protein. These mutations are heterozygous and autosomal dominant [15, 84, 85]. Two different mouse models of CUL3 have been reported, to date.…”

Section: Cul3–klhl3 As Upstream Regulators Of Wnk Kinasesmentioning

confidence: 99%

WNK signalling pathways in blood pressure regulation

Murthy

Kurz

O’Shaughnessy

2016

Cell. Mol. Life Sci.

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“…47 However, faced with only mild hyperkalemia, the only certain way to diagnose PHAII is to do genetic studies. Thus, Osawa et al 48 in 2013 found a mutant cullin3 (CUL3; see below) in a 1-yearold boy with hypertension and mild hyperkalemia, which sealed the diagnosis of PHAII.…”

Section: Hypertensionmentioning

confidence: 98%

Pseudohypoaldosteronism Type II

Healy

2014

Hypertension

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K + during a NaHCO 3 infusion. As will be discussed below, we now know that there are 5 levels of severity of PHAII so that the response to PRAN may differ between individual cases. Given the hyperkalemia of these patients, one might have expected even a supranormal response to PRAN as seen below in the mouse model of PHAII.32 PRAN were used in 11 of the studies surveyed here and although some had a reduced kaliuretic response, in none was there a response greater than the normal controls. 3,5,[7][8][9][11][12][13]17,19,20 Therefore, given the hyperkalemia, these results indicate a mild degree of depression of ENaC function. This might have been expected to lead to a compensatory increase in activity of the major K + secretory mechanism, the renal outer medullary K + (ROMK) channels. 34,35 This might imply that ROMK also was not functioning normally (Figure, Theory 1).Another factor that could have suppressed the K + secretion, particularly ROMK, 31 was the acidosis, which is known to be because of hyperkalemia in PHAII. 5,7,11,12 If PHAII is reversed by drug treatment (thiazide) and the drug is stopped, the hyperkalemia returns in 10 days before a return of the acidosis at 17 days, 8 indicating the primacy of the hyperkalemia. If the ENaC is compromised to a degree, this period without acidosis would provide ROMK with a window of opportunity to control the rising plasma K + ; this clearly does not happen. DeFronzo et al 33 studied K + secretion in sickle cell disease that damages the renal papillae and the medulla. They found a negligible response in K + secretion to PRAN, yet hyperkalemia did not occur (average plasma K + , 3.78±0.01 mmol/L). This difference from PHAII might be explained by the fact that although ROMK shares the late DT, the connecting tubule and the collecting duct sites with ENaC, functioning isoforms ROMK 2 and 3 are present as well in the whole of the distal convoluted tubule (DCT). 34 Therefore, in sickle cell disease, these isoforms may have been intact in the DCT before the late DCT but perhaps not so in PHAII. PHAII and sickle cell disease cannot be compared pathologically, but these results reflect on the way the effects of PRAN are interpreted because they show that a negligible response in K + secretion to PRAN is not obligatorily associated with hyperkalemia in humans.Finally, Golbang et al 26 (see below) have described a father and son with PHAII caused by a mutant gene shown by genetic testing to inhibit ROMK substantially.The second view of the cause of hyperkalemia in PHAII is that a Cl -shunt may play a role 3 by increasing paracellular Cl -absorption in the early DT (Figure, Theory 2). Schambelan et al 3 in 1981 showed that with mineralocorticoid pretreatment, intravenous Na 2 SO 4 and NaHCO 3 could both invoke an increase in K + excretion in PHAII, but that intravenous sodium chloride (NaCl) was much less able to do so. They postulated that a Cl -shunt proximal to the ENaC would result in less Cl -delivery and thus less negativity at the ENaC, resulting in decreased K + sec...

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“…Increased expression of CUL3 (Cullin 3) in the caudate basal ganglia was associated with increased risk of AN in our study (OR=1.07). Dysregulation of CUL3 is associated with pseudohypoaldosteronism 77 , a disorder characterized by sodium imbalance in the body and often presenting with low body weight. Mutations in CUL3 are associated with schizophrenia 78 , autism 79 and non-response to anti-depressants 80 .…”

Section: Discussionmentioning

confidence: 99%

Identifying tissues implicated in Anorexia Nervosa using Transcriptomic Imputation

Dobbyn

McFadden

et al. 2018

Preprint

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Anorexia nervosa (AN) is a complex and serious eating disorder, occurring in ~1% of individuals. Despite having the highest mortality rate of any psychiatric disorder, little is known about the aetiology of AN, and few effective treatments exist.Global efforts to collect large sample sizes of individuals with AN have been highly successful, and a recent study consequently identified the first genome-wide significant locus involved in AN. This result, coupled with other recent studies and epidemiological evidence, suggest that previous characterizations of AN as a purely psychiatric disorder are over-simplified. Rather, both neurological and metabolic pathways may also be involved.In order to elucidate more of the system-specific aetiology of AN, we applied transcriptomic imputation methods to 3,495 cases and 10,982 controls, collected by the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED). Transcriptomic Imputation (TI) methods approaches use machine-learning methods to impute tissue-specific gene expression from large genotype data using curated eQTL reference panels. These offer an exciting opportunity to compare gene associations across neurological and metabolic tissues. Here, we applied CommonMind Consortium (CMC) and GTEx-derived gene expression prediction models for 13 brain tissues and 12 tissues with potential metabolic involvement (adipose, adrenal gland, 2 colon, 3 esophagus, liver, pancreas, small intestine, spleen, stomach).We identified 35 significant gene-tissue associations within the large chromosome 12 region described in the recent PGC-ED GWAS. We applied forward stepwise conditional analyses and FINEMAP to associations within this locus to identify putatively causal signals. We identified four independently associated genes; RPS26, C12orf49, SUOX, and RDH16. We also identified two further genome-wide significant gene-tissue associations, both in brain tissues; REEP5, in the dorso-lateral pre-frontal cortex (DLPFC; p=8.52×10−07), and CUL3, in the caudate basal ganglia (p=1.8×10−06). These genes are significantly enriched for associations with anthropometric phenotypes in the UK BioBank, as well as multiple psychiatric, addiction, and appetite/satiety pathways. Our results support a model of AN risk influenced by both metabolic and psychiatric factors.

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CUL3 gene analysis enables early intervention for pediatric pseudohypoaldosteronism type II in infancy

Abstract: Since chronic acidosis and hypertension associated with PHA-II can result in delayed growth and development in pediatric patients, genetic analysis to detect the CUL3 mutation and to enable intervention early in the disease course would be beneficial for infants with suspected PHA-II.

Cited by 25 publications

References 6 publications

WNK signalling pathways in blood pressure regulation

WNK signalling pathways in blood pressure regulation

Pseudohypoaldosteronism Type II

Identifying tissues implicated in Anorexia Nervosa using Transcriptomic Imputation

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