OR40-2 Detection of mutations in KLHL3 and CUL3 in families with Familial Hyperkalaemic Hypertension (FHH or Gordon syndrome)

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR40-Renin-Angiotensin-Aldosterone System/Endocrine Hypertension
Basic/Clinical
Monday, June 17, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 11:30 AM
Room 135 (Moscone Center)
Mark Glover*1, James Ware2, Amanda Henry1, Martin Wolley3, Shengxin Xu3, Stuart Cook2, Ian Hall1, Richard Gordon3, Michael Stowasser3 and Kevin O'Shaughnessy4
1University of Nottingham, Nottingham, United Kingdom, 2Imperial College, London, United Kingdom, 3University of Queensland, Brisbane, Australia, 4University of Cambridge, Cambridge, United Kingdom
Familial Hyperkalemic Hypertension (FHH, Gordon Syndrome) is a salt-dependent hypertension with suppressed renin causing a false positive raised aldosterone/renin ratio when screening for primary aldosteronism1. FHH is a genetically heterogeneous condition caused by mutations in regulators of the thiazide-sensitive NaCl cotransporter, NCC, and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes  can cause FHH, including ‘With No lysine (K)’ kinases (WNK1 and WNK4) and, more recently, KeLcH-Like3 (KLHL3) and CULlin3 (CUL3)2,3. Here we report the genetic analysis of 25 affected individuals from 16 families with FHH who had already been screened and found negative for WNK1/4 mutations.

CUL3 and KLHL3 were sequenced using PCR-based enrichment of all coding exons (Fluidigm Access Array), followed by sequencing on the Illumina HiSeq platform. GATK variant calling followed by within family filtering and comparison with publically available and in-house genetic databases was used to prioritise variants. Sanger sequencing was used to validate NGS results. Human genome build hg19 was used to denote coordinates.

Affecteds (n=16) from 10 of 16 families were found to have CUL3 or KLHL3 variants not reported in the general population. Seven families (2 with CUL3, 5 with KLHL3 mutations) demonstrated mutations previously associated with FHH. Previously undescribed mutations were discovered in three families (2 with CUL3 [g.225368551 T>A and g.225368368 G>T] and 1 with KLHL3 mutation [g.136964078 G>T, causing ENSP00000312397 p.G500V]). In keeping with previous observations, CUL3 mutations were intronic and likely affect splicing of exon 9, whereas KLHL3 mutations were non-synonymous exonic SNPs.  

Our results confirm recent findings of CUL3 and KLHL3 mutations in FHH2,3 and identify novel disease-causing variants. This strengthens the argument that these gene products are physiologically important regulators of distal nephron NaCl reabsorption via thiazide-sensitive pathways, and hence are potentially interesting novel anti-hypertensive drug targets. As only 63% of our non-WNK FHH families were found to contain plausible CUL3 or KLHL3 variants, there are likely to be additional, as yet undiscovered, regulators of thiazide-sensitive pathways.

1. Gordon RD. Hypertension. 1986;8:93-102 2. Boyden et al. Nature. 2012;482(7383):98-102.  3. Louis-Dit-Picard et al. Nat Genet. 2012;44:456-460.

Nothing to Disclose: MG, JW, AH, MW, SX, SC, IH, RG, MS, KO

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