Andersen-Tawil syndrome: new potassium channel mutations and possible phenotypic variation.
OBJECTIVE
To evaluate clinical, genetic, and electrophysiologic features of patients with Andersen-Tawil syndrome (ATS) in the United Kingdom.


METHODS
Clinical and neurophysiologic evaluation was conducted of 11 families suspected to have ATS. Molecular genetic analysis of each proband was performed by direct DNA sequencing of the entire coding region of KCNJ2. Control samples were screened by direct DNA sequencing. The electrophysiologic consequences of several new mutations were studied in an oocyte expression system.


RESULTS
All 11 ATS families harbored pathogenic mutations in KCNJ2 with six mutations not previously reported. Some unusual clinical features including renal tubular defect, CNS involvement, and dental and phonation abnormalities were observed. Five mutations (T75M, D78G, R82Q, L217P, and G300D) were expressed, all of which resulted in nonfunctional channels when expressed alone, and co-expression with wild-type (WT) KCNJ2 demonstrated a dominant negative effect.


CONCLUSIONS
Six new disease-causing mutations in KCNJ2 were identified, one of which was in a PIP2 binding site. Molecular expression studies indicated that five of the mutations exerted a dominant negative effect on the wild-type allele. KCNJ2 mutations are an important cause of ATS in the UK.
Davies
N P
NP
Muscle and Nerve Centre, Queen Elizabeth Hospital, University of Birmingham NHS Trust, UK.
Imbrici
P
P
Fialho
D
D
Herd
C
C
Bilsland
L G
LG
Weber
A
A
Mueller
R
R
Hilton-Jones
D
D
Ealing
J
J
Boothman
B R
BR
Giunti
P
P
Parsons
L M
LM
Thomas
M
M
Manzur
A Y
AY
Jurkat-Rott
K
K
Lehmann-Horn
F
F
Chinnery
P F
PF
Rose
M
M
Kullmann
D M
DM
Hanna
M G
MG
D000293:Adolescent; D000328:Adult; D050030:Andersen Syndrome / Q000235:genetics* / Q000503:physiopathology; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007684:Kidney Tubules / Q000002:abnormalities; D008297:Male; D009154:Mutation / Q000235:genetics*; D009865:Oocytes; D010641:Phenotype; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics; D014071:Tooth Abnormalities / Q000235:genetics; D014982:Xenopus laevis
C489457:KCNJ2 protein, human; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying