PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome.
BACKGROUND
Mutations in KCNJ2, the gene encoding the inward-rectifying K+ channel Kir2.1, cause the cardiac, skeletal muscle, and developmental phenotypes of Andersen-Tawil syndrome (ATS; also known as Andersen syndrome). Although pathogenic mechanisms have been proposed for select mutations, a common mechanism has not been identified.


METHODS
Seventeen probands presenting with symptoms characteristic of ATS were evaluated clinically and screened for mutations in KCNJ2. The results of mutation analysis were combined with those from previously studied subjects to assess the frequency with which KCNJ2 mutations cause ATS.


RESULTS
Mutations in KCNJ2 were discovered in nine probands. These included six novel mutations (D71N, T75R, G146D, R189I, G300D, and R312C) as well as previously reported mutations R67W and R218W. Six probands possessed mutations of residues implicated in binding membrane-associated phosphatidylinositol 4,5-bisphosphate (PIP2). In total, mutations in PIP(2)-related residues accounted for disease in 18 of 29 (62%) reported KCNJ2 -based probands with ATS. Also reported is that mutation R67W causes the full clinical triad in two unrelated males.


CONCLUSIONS
The novel mutations corresponding to residues involved in Kir2.1 channel-PIP2 interactions presented here as well as the overall frequency of mutations occurring in these residues indicate that defects in PIP2 binding constitute a major pathogenic mechanism of ATS. Furthermore, screening KCNJ2 in patients with the complex phenotypes of ATS was found to be invaluable in establishing or confirming a disease diagnosis as mutations in this gene can be identified in the majority of patients.
Donaldson
M R
MR
Department of Human Genetics and Molecular Biology, University of Utah, Salt Lake City, USA.
Jensen
J L
JL
Tristani-Firouzi
M
M
Tawil
R
R
Bendahhou
S
S
Suarez
W A
WA
Cobo
A M
AM
Poza
J J
JJ
Behr
E
E
Wagstaff
J
J
Szepetowski
P
P
Pereira
S
S
Mozaffar
T
T
Escolar
D M
DM
Fu
Y-H
YH
Ptácek
L J
LJ
D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000235:genetics*; D001665:Binding Sites; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018908:Muscle Weakness / Q000235:genetics; D009154:Mutation; D010243:Paralysis / Q000175:diagnosis / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
D019269:Phosphatidylinositol 4,5-Diphosphate; D024661:Potassium Channels, Inwardly Rectifying