Familial Hyperkalemia and Hypertension (FHHt) and KLHL3: Description of a Family with a New Recessive Mutation (S553L) Compared to a Family with a Dominant Mutation, Q309R, with Analysis of Urinary Sodium Chloride Cotransporter

Abstract

Background: Familial hyperkalemia and hypertension (FHHt) is an inherited disorder manifested by hyperkalemia and hypertension. The following four causative genes were identified: WNK1, WNK4, CUL3, and KLHL3. For the first 3 genes, inheritance is autosomal dominant. For KLHL3, inheritance is mostly dominant. A few cases with autosomal recessive disease were described. The mechanism of these 2 modes of inheritance is not clear. In the recessive form, the phenotype of heterozygotes is not well described. Methods: Clinical and genetic investigation of members of 2 families was performed, one with recessive FHHt, and the other, an expansion of a family with Q309R KLHL3 dominant mutation, previously reported by us. Urinary exosomal sodium chloride cotransporter (NCC) was measured. Results: A family with recessive FHHt caused by a new KLHL3 mutation, S553L, is described. This consanguineous Jewish family of Yemenite extraction, included 2 homozygous and 7 heterozygous affected subjects. Increased urinary NCC was found in the affected members of the family with dominant Q309R KLHL3 mutation. In the recessive S553L family, homozygotes appeared to have increased urinary NCC abundance. Surprisingly, heterozygotes seemed to have also increased urinary NCC, though at an apparently lower degree. This was not accompanied by a clinical phenotype. Conclusions: A new recessive mutation in KLHL3 (S553L) was identified in FHHt. Increased urinary NCC was found in affected members (heterozygous) with dominant KLHL3 Q309R, and in affected members (homozygous) of the recessive form. Unexpectedly, in the recessive disease, heterozygotes seemed to have increased urinary NCC as well, apparently not sufficient quantitatively to produce a clinical phenotype.

A Novel Homozygous <b><i>KLHL3</i></b> Mutation as a Cause of Autosomal Recessive Pseudohypoaldosteronism Type II Diagnosed Late in Life

“…Hyperkalemia despite a normal glomerular filtration rate is often described as a characteristic feature of PHA II [ 6 ]. While this may be characteristic in children, in adults, such as in the patient reported here, longstanding hypertension, nephrolithiasis, and recurrent urinary tract infections can lead to impaired kidney function, as previously reported in a patient with a heterozygous mutation [ 14 ]. Nephrolithiasis as in our patient has been described in PHA II [ 50 ] but is not a common finding.…”

“…Dominant KLHL3 mutations cluster in or between propeller blades, whereas recessive mutations are distributed throughout the protein [ 12 ]. Recessive cases are less common than dominant cases; in total, 21 patients from 14 families with recessive KLHL3 mutations have been published [ 12 , 13 , 14 , 15 ] (Table 1 ).…”

The variety of genetic defects explains the phenotypic heterogeneity of Familial Hyperkalemic Hypertension

“…Clinical experience from our center, combined with published results [6,23] suggested the absence or a very moderate FHHt phenotype in heterozygous relatives in families with KLHL3 AR. Expression variability was studied by comparing clinical and biological phenotypes of the following four groups: i) relatives wild-type of KLHL3 AD, ii) relatives heterozygous of KLHL3 AR, iii) patients KLHL3 AD, and iv) patients (homozygous or compound heterozygous) KLHL3 AR.…”

A case report of pseudohypoaldosteronism type II with a homozygous KLHL3 variant accompanied by hyperthyroidism

“…However, we cannot confirm this hypothesis without pedigree research. Most previous case reports of PHAII were in children or young adults, but there have been adults who were diagnosed later in life[ 12 , 13 ]. It is not clear why some mutations of KLHL3 can cause PHAII at an advanced age.…”