Session: OR40-Renin-Angiotensin-Aldosterone System/Endocrine Hypertension
Room 135 (Moscone Center)
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.
Nothing to Disclose: MG, JW, AH, MW, SX, SC, IH, RG, MS, KO
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