PHA2D
MCID: PSD093
MIFTS: 32

Pseudohypoaldosteronism, Type Iid (PHA2D)

Categories: Blood diseases, Cardiovascular diseases, Genetic diseases, Metabolic diseases, Nephrological diseases, Rare diseases

Aliases & Classifications for Pseudohypoaldosteronism, Type Iid

MalaCards integrated aliases for Pseudohypoaldosteronism, Type Iid:

Name: Pseudohypoaldosteronism, Type Iid 57 13 70
Pseudohypoaldosteronism Type 2d 58 29 6 39
Pha2d 57 58 72
Familial Hyperkalemic Hypertension; Fhht 57
Familial Hyperkalemic Hypertension 57
Pseudohypoaldosteronism 2d 72
Fhht 57

Characteristics:

Orphanet epidemiological data:

58
pseudohypoaldosteronism type 2d
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide);

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal recessive
autosomal dominant

Miscellaneous:
responsive to thiazide diuretics
40 patients in 16 dominant kindreds reported (as of february 2012)
14 patients in 8 recessive kindreds reported (as of february 2012)
less than 20% have onset at 18 years of age or less (dominant and recessive)
age at diagnosis 24 +/- 18 years for dominant disease
age at diagnosis 26 +/- 14 years for recessive disease


HPO:

31
pseudohypoaldosteronism, type iid:
Inheritance autosomal dominant inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare circulatory system diseases
Rare renal diseases


External Ids:

OMIM® 57 614495
OMIM Phenotypic Series 57 PS145260
MeSH 44 D011546
ICD10 via Orphanet 33 I15.1
Orphanet 58 ORPHA300525
MedGen 41 C3469605
UMLS 70 C3469605

Summaries for Pseudohypoaldosteronism, Type Iid

OMIM® : 57 Familial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (summary by Louis-Dit-Picard et al., 2012). (614495) (Updated 05-Apr-2021)

MalaCards based summary : Pseudohypoaldosteronism, Type Iid, also known as pseudohypoaldosteronism type 2d, is related to pseudohypoaldosteronism, type iie and metabolic acidosis. An important gene associated with Pseudohypoaldosteronism, Type Iid is KLHL3 (Kelch Like Family Member 3). Affiliated tissues include kidney, and related phenotypes are hypertension and hyperkalemia

UniProtKB/Swiss-Prot : 72 Pseudohypoaldosteronism 2D: A disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics. PHA2D inheritance is autosomal dominant or recessive.

Related Diseases for Pseudohypoaldosteronism, Type Iid

Graphical network of the top 20 diseases related to Pseudohypoaldosteronism, Type Iid:



Diseases related to Pseudohypoaldosteronism, Type Iid

Symptoms & Phenotypes for Pseudohypoaldosteronism, Type Iid

Human phenotypes related to Pseudohypoaldosteronism, Type Iid:

31
# Description HPO Frequency HPO Source Accession
1 hypertension 31 HP:0000822
2 hyperkalemia 31 HP:0002153
3 hyperchloremic metabolic acidosis 31 HP:0004918
4 pseudohypoaldosteronism 31 HP:0008242
5 hyperchloremia 31 HP:0011423

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Cardiovascular Vascular:
hypertension

Laboratory Abnormalities:
hyperkalemia (>6.2 mm in both dominant and recessive)
hyperchloremia (mean >110 mm in both dominant and recessive)

Metabolic Features:
hyperchloremic metabolic acidosis (hco3 17.2 +/- 2.5 mm, dominant)
hyperchloremic metabolic acidosis (hco3 17.6 +/- 1.5 mm, recessive)

Clinical features from OMIM®:

614495 (Updated 05-Apr-2021)

Drugs & Therapeutics for Pseudohypoaldosteronism, Type Iid

Search Clinical Trials , NIH Clinical Center for Pseudohypoaldosteronism, Type Iid

Genetic Tests for Pseudohypoaldosteronism, Type Iid

Genetic tests related to Pseudohypoaldosteronism, Type Iid:

# Genetic test Affiliating Genes
1 Pseudohypoaldosteronism Type 2d 29 KLHL3

Anatomical Context for Pseudohypoaldosteronism, Type Iid

MalaCards organs/tissues related to Pseudohypoaldosteronism, Type Iid:

40
Kidney

Publications for Pseudohypoaldosteronism, Type Iid

Articles related to Pseudohypoaldosteronism, Type Iid:

(show all 43)
# Title Authors PMID Year
1
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. 57 6 61
22406640 2012
2
Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. 6 57
24821705 2014
3
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. 6 57
22266938 2012
4
Decreased KLHL3 expression is involved in the activation of WNK-OSR1/SPAK-NCC cascade in type 1 diabetic mice. 61
33432425 2021
5
Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis. 61
32790646 2020
6
Cullin-3: Renal and Vascular Mechanisms Regulating Blood Pressure. 61
32852625 2020
7
Hypertension-causing cullin 3 mutations disrupt COP9 signalosome binding. 61
31813255 2020
8
Hyperkalemia and blood pressure regulation. 61
31800077 2019
9
The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway. 61
30723251 2019
10
Severe Arterial Hypertension from Cullin 3 Mutations Is Caused by Both Renal and Vascular Effects. 61
30967423 2019
11
Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway. 61
30301860 2018
12
Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. 61
29846116 2018
13
Renal Mg handling, FXYD2 and the central role of the Na,K-ATPase. 61
30175537 2018
14
Mechanisms and controversies in mutant Cul3-mediated familial hyperkalemic hypertension. 61
29361671 2018
15
Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4. 61
29459793 2018
16
Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. 61
29263298 2017
17
Constitutively Active SPAK Causes Hyperkalemia by Activating NCC and Remodeling Distal Tubules. 61
28442491 2017
18
WNK signalling pathways in blood pressure regulation. 61
27815594 2017
19
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. 61
28511177 2017
20
Hyperkalemia in young children: blood pressure checked? 61
27639857 2016
21
ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation. 61
27378813 2016
22
[New perspective on the role of WNK1 and WNK4 in the regulation of NaCl reabsorption and K(+) secretion by the distal nephron]. 61
27011246 2016
23
Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension. 61
26607111 2016
24
Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia. 61
26286618 2015
25
Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations. 61
25925082 2015
26
Hyperkalemic hypertension-associated cullin 3 promotes WNK signaling by degrading KLHL3. 61
25250572 2014
27
WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. 61
25113964 2014
28
Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome). 61
24266877 2014
29
A molecular update on pseudohypoaldosteronism type II. 61
24107425 2013
30
Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase. 61
23885063 2013
31
WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. 61
23940364 2013
32
A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms. 61
22701532 2012
33
Overexpression of the sodium chloride cotransporter is not sufficient to cause familial hyperkalemic hypertension. 61
21896937 2011
34
Cyclosporine metabolic side effects: association with the WNK4 system. 61
21434893 2011
35
Effect of age and affection status on blood pressure, serum potassium and stature in familial hyperkalaemia and hypertension. 61
20956807 2011
36
Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension. 61
20921400 2010
37
Familial hyperkalemia and hypertension: pathogenetic insights based on lithium clearance. 61
19491230 2009
38
The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. 61
17975670 2007
39
Dehydrated hereditary stomatocytosis mimicking familial hyperkalaemic hypertension: clinical and genetic investigation. 61
17253968 2007
40
WNK1 and WNK4 modulate CFTR activity. 61
17194447 2007
41
Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. 61
16899520 2006
42
Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. 61
16204408 2006
43
Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. 61
15841204 2005

Variations for Pseudohypoaldosteronism, Type Iid

ClinVar genetic disease variations for Pseudohypoaldosteronism, Type Iid:

6 (show top 50) (show all 129)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 KLHL3 KLHL3, TRP470TER SNV Pathogenic 30515 GRCh37:
GRCh38:
2 KLHL3 NM_017415.3(KLHL3):c.965T>G (p.Phe322Cys) SNV Pathogenic 30516 rs199469639 GRCh37: 5:136975605-136975605
GRCh38: 5:137639916-137639916
3 KLHL3 NM_017415.3(KLHL3):c.1229C>T (p.Ser410Leu) SNV Pathogenic 30517 rs199469641 GRCh37: 5:136973075-136973075
GRCh38: 5:137637386-137637386
4 KLHL3 NM_017415.3(KLHL3):c.1583G>A (p.Arg528His) SNV Pathogenic 30518 rs199469636 GRCh37: 5:136963994-136963994
GRCh38: 5:137628305-137628305
5 KLHL3 NM_017415.3(KLHL3):c.718C>T (p.Arg240Ter) SNV Pathogenic 30519 rs199469638 GRCh37: 5:136997639-136997639
GRCh38: 5:137661950-137661950
6 KLHL3 NM_017415.3(KLHL3):c.1007G>T (p.Arg336Ile) SNV Pathogenic 30520 rs199469640 GRCh37: 5:136975563-136975563
GRCh38: 5:137639874-137639874
7 KLHL3 NM_017415.3(KLHL3):c.1670A>G (p.Tyr557Cys) SNV Pathogenic 30521 rs199469645 GRCh37: 5:136961507-136961507
GRCh38: 5:137625818-137625818
8 KLHL3 NM_017415.3(KLHL3):c.1582C>T (p.Arg528Cys) SNV Pathogenic 30522 rs199469635 GRCh37: 5:136963995-136963995
GRCh38: 5:137628306-137628306
9 KLHL3 NM_017415.3(KLHL3):c.1298G>A (p.Ser433Asn) SNV Pathogenic 30523 rs199469632 GRCh37: 5:136973006-136973006
GRCh38: 5:137637317-137637317
10 KLHL3 NM_017415.3(KLHL3):c.1193C>T (p.Ala398Val) SNV Pathogenic 31544 rs387907155 GRCh37: 5:136974668-136974668
GRCh38: 5:137638979-137638979
11 KLHL3 NM_017415.3(KLHL3):c.1587C>A (p.Asn529Lys) SNV Pathogenic 31545 rs562736621 GRCh37: 5:136963990-136963990
GRCh38: 5:137628301-137628301
12 KLHL3 NM_017415.3(KLHL3):c.1277C>T (p.Pro426Leu) SNV Pathogenic 31546 rs387907156 GRCh37: 5:136973027-136973027
GRCh38: 5:137637338-137637338
13 KLHL3 NM_017415.3(KLHL3):c.1512del (p.Lys505fs) Deletion Pathogenic 1032742 GRCh37: 5:136964065-136964065
GRCh38: 5:137628376-137628376
14 KLHL3 NM_017415.3(KLHL3):c.1519G>A (p.Val507Ile) SNV Likely pathogenic 217888 rs863225302 GRCh37: 5:136964058-136964058
GRCh38: 5:137628369-137628369
15 KLHL3 NM_017415.3(KLHL3):c.1694C>T (p.Thr565Met) SNV Uncertain significance 634612 rs375871642 GRCh37: 5:136961483-136961483
GRCh38: 5:137625794-137625794
16 KLHL3 NM_017415.3(KLHL3):c.730T>C (p.Leu244=) SNV Uncertain significance 903678 GRCh37: 5:136997627-136997627
GRCh38: 5:137661938-137661938
17 KLHL3 NM_017415.3(KLHL3):c.-402C>T SNV Uncertain significance 351004 rs774532097 GRCh37: 5:137071737-137071737
GRCh38: 5:137736048-137736048
18 KLHL3 NM_017415.3(KLHL3):c.*4364A>G SNV Uncertain significance 350920 rs886059935 GRCh37: 5:136953423-136953423
GRCh38: 5:137617734-137617734
19 KLHL3 NM_017415.3(KLHL3):c.*4356G>T SNV Uncertain significance 350921 rs757402685 GRCh37: 5:136953431-136953431
GRCh38: 5:137617742-137617742
20 KLHL3 NM_017415.3(KLHL3):c.*4257A>G SNV Uncertain significance 350922 rs768556632 GRCh37: 5:136953530-136953530
GRCh38: 5:137617841-137617841
21 KLHL3 NM_017415.3(KLHL3):c.*4202G>C SNV Uncertain significance 904613 GRCh37: 5:136953585-136953585
GRCh38: 5:137617896-137617896
22 KLHL3 NM_017415.3(KLHL3):c.*4185G>A SNV Uncertain significance 904614 GRCh37: 5:136953602-136953602
GRCh38: 5:137617913-137617913
23 KLHL3 NM_017415.3(KLHL3):c.*2763C>T SNV Uncertain significance 350945 rs550345984 GRCh37: 5:136955024-136955024
GRCh38: 5:137619335-137619335
24 KLHL3 NM_017415.3(KLHL3):c.*2692C>T SNV Uncertain significance 904676 GRCh37: 5:136955095-136955095
GRCh38: 5:137619406-137619406
25 KLHL3 NM_017415.3(KLHL3):c.*2647C>T SNV Uncertain significance 904677 GRCh37: 5:136955140-136955140
GRCh38: 5:137619451-137619451
26 KLHL3 NM_017415.3(KLHL3):c.*2472A>C SNV Uncertain significance 350948 rs886059944 GRCh37: 5:136955315-136955315
GRCh38: 5:137619626-137619626
27 KLHL3 NM_017415.3(KLHL3):c.*2448C>T SNV Uncertain significance 350949 rs886059945 GRCh37: 5:136955339-136955339
GRCh38: 5:137619650-137619650
28 KLHL3 NM_017415.3(KLHL3):c.*748T>C SNV Uncertain significance 350971 rs886059952 GRCh37: 5:136957039-136957039
GRCh38: 5:137621350-137621350
29 KLHL3 NM_017415.3(KLHL3):c.*681C>T SNV Uncertain significance 904752 GRCh37: 5:136957106-136957106
GRCh38: 5:137621417-137621417
30 KLHL3 NM_017415.3(KLHL3):c.*539G>A SNV Uncertain significance 350973 rs886059954 GRCh37: 5:136957248-136957248
GRCh38: 5:137621559-137621559
31 KLHL3 NM_017415.3(KLHL3):c.*501T>C SNV Uncertain significance 350974 rs886059955 GRCh37: 5:136957286-136957286
GRCh38: 5:137621597-137621597
32 KLHL3 NM_017415.3(KLHL3):c.*481G>A SNV Uncertain significance 350975 rs886059956 GRCh37: 5:136957306-136957306
GRCh38: 5:137621617-137621617
33 KLHL3 NM_017415.3(KLHL3):c.*4166T>C SNV Uncertain significance 905401 GRCh37: 5:136953621-136953621
GRCh38: 5:137617932-137617932
34 KLHL3 NM_017415.3(KLHL3):c.*4080C>T SNV Uncertain significance 905402 GRCh37: 5:136953707-136953707
GRCh38: 5:137618018-137618018
35 KLHL3 NM_017415.3(KLHL3):c.*4066C>T SNV Uncertain significance 350924 rs544519958 GRCh37: 5:136953721-136953721
GRCh38: 5:137618032-137618032
36 KLHL3 NM_017415.3(KLHL3):c.*1034C>T SNV Uncertain significance 350969 rs886059951 GRCh37: 5:136956753-136956753
GRCh38: 5:137621064-137621064
37 KLHL3 NM_017415.3(KLHL3):c.*953A>G SNV Uncertain significance 904751 GRCh37: 5:136956834-136956834
GRCh38: 5:137621145-137621145
38 KLHL3 NM_017415.3(KLHL3):c.*3920T>G SNV Uncertain significance 350927 rs886059936 GRCh37: 5:136953867-136953867
GRCh38: 5:137618178-137618178
39 KLHL3 NM_017415.3(KLHL3):c.*3913A>T SNV Uncertain significance 905403 GRCh37: 5:136953874-136953874
GRCh38: 5:137618185-137618185
40 KLHL3 NM_017415.3(KLHL3):c.*2360G>A SNV Uncertain significance 350951 rs533076689 GRCh37: 5:136955427-136955427
GRCh38: 5:137619738-137619738
41 KLHL3 NM_017415.3(KLHL3):c.*2337A>G SNV Uncertain significance 905467 GRCh37: 5:136955450-136955450
GRCh38: 5:137619761-137619761
42 KLHL3 NM_017415.3(KLHL3):c.*2168T>C SNV Uncertain significance 350954 rs886059946 GRCh37: 5:136955619-136955619
GRCh38: 5:137619930-137619930
43 KLHL3 NM_017415.3(KLHL3):c.*2156A>G SNV Uncertain significance 350955 rs886059947 GRCh37: 5:136955631-136955631
GRCh38: 5:137619942-137619942
44 KLHL3 NM_017415.3(KLHL3):c.*2088C>T SNV Uncertain significance 905468 GRCh37: 5:136955699-136955699
GRCh38: 5:137620010-137620010
45 KLHL3 NM_017415.3(KLHL3):c.*299G>A SNV Uncertain significance 350978 rs539132895 GRCh37: 5:136957488-136957488
GRCh38: 5:137621799-137621799
46 KLHL3 NM_017415.3(KLHL3):c.*224G>T SNV Uncertain significance 350979 rs536807069 GRCh37: 5:136957563-136957563
GRCh38: 5:137621874-137621874
47 KLHL3 NM_017415.3(KLHL3):c.*174C>G SNV Uncertain significance 905542 GRCh37: 5:136957613-136957613
GRCh38: 5:137621924-137621924
48 KLHL3 NM_017415.3(KLHL3):c.*149G>A SNV Uncertain significance 350980 rs886059957 GRCh37: 5:136957638-136957638
GRCh38: 5:137621949-137621949
49 KLHL3 NM_017415.3(KLHL3):c.1725G>A (p.Arg575=) SNV Uncertain significance 905543 GRCh37: 5:136961452-136961452
GRCh38: 5:137625763-137625763
50 KLHL3 NM_017415.3(KLHL3):c.*3473T>C SNV Uncertain significance 350928 rs886059937 GRCh37: 5:136954314-136954314
GRCh38: 5:137618625-137618625

UniProtKB/Swiss-Prot genetic disease variations for Pseudohypoaldosteronism, Type Iid:

72 (show all 32)
# Symbol AA change Variation ID SNP ID
1 KLHL3 p.Ala77Glu VAR_067501 rs199469623
2 KLHL3 p.Met78Val VAR_067502 rs199469624
3 KLHL3 p.Glu85Ala VAR_067503 rs199469625
4 KLHL3 p.Cys164Phe VAR_067504 rs199469626
5 KLHL3 p.Arg228Gly VAR_067505
6 KLHL3 p.Gln309Arg VAR_067506 rs199469627
7 KLHL3 p.Phe322Cys VAR_067507 rs199469639
8 KLHL3 p.Arg336Ile VAR_067508 rs199469640
9 KLHL3 p.Ala340Val VAR_067509 rs199469628
10 KLHL3 p.Val361Met VAR_067510
11 KLHL3 p.Arg362Trp VAR_067511 rs200892557
12 KLHL3 p.Arg384Gln VAR_067512 rs199469629
13 KLHL3 p.Arg384Trp VAR_067513 rs951676369
14 KLHL3 p.Leu387Pro VAR_067514 rs199469630
15 KLHL3 p.Ala398Val VAR_067515 rs387907155
16 KLHL3 p.Ser410Leu VAR_067516 rs199469641
17 KLHL3 p.Pro426Leu VAR_067517 rs387907156
18 KLHL3 p.Met427Thr VAR_067518 rs199469642
19 KLHL3 p.Arg431Gln VAR_067519 rs199469643
20 KLHL3 p.Ser432Asn VAR_067520 rs199469631
21 KLHL3 p.Ser433Gly VAR_067521
22 KLHL3 p.Ser433Asn VAR_067522 rs199469632
23 KLHL3 p.Ala494Thr VAR_067524 rs199469633
24 KLHL3 p.Gly500Val VAR_067525 rs746774345
25 KLHL3 p.Pro501Thr VAR_067526 rs199469634
26 KLHL3 p.Arg528Cys VAR_067527 rs199469635
27 KLHL3 p.Arg528His VAR_067528 rs199469636
28 KLHL3 p.Asn529Lys VAR_067529
29 KLHL3 p.Tyr557Cys VAR_067530 rs199469645
30 KLHL3 p.Arg575Trp VAR_067531 rs199469646
31 KLHL3 p.His498Tyr VAR_079630
32 KLHL3 p.Ser553Leu VAR_079631 rs136718489

Expression for Pseudohypoaldosteronism, Type Iid

Search GEO for disease gene expression data for Pseudohypoaldosteronism, Type Iid.

Pathways for Pseudohypoaldosteronism, Type Iid

GO Terms for Pseudohypoaldosteronism, Type Iid

Sources for Pseudohypoaldosteronism, Type Iid

3 CDC
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