Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.
BACKGROUND
Action myoclonus-renal failure syndrome is a hereditary form of progressive myoclonus epilepsy associated with renal failure. It is considered to be an autosomal-recessive disease related to loss-of-function mutations in SCARB2. We studied a German AMRF family, additionally showing signs of demyelinating polyneuropathy and dilated cardiomyopathy. To test the hypothesis whether isolated appearance of individual AMRF syndrome features could be related to heterozygote SCARB2 mutations, we screened for SCARB2 mutations in unrelated patients showing isolated AMRF features.


METHODS
In the AMRF family all exons of SCARB2 were analyzed by Sanger sequencing. The mutation screening of unrelated patients with isolated AMRF features affected by either epilepsy (n = 103, progressive myoclonus epilepsy or generalized epilepsy), demyelinating polyneuropathy (n = 103), renal failure (n = 192) or dilated cardiomyopathy (n = 85) was performed as high resolution melting curve analysis of the SCARB2 exons.


RESULTS
A novel homozygous 1 bp deletion (c.111delC) in SCARB2 was found by sequencing three affected homozygous siblings of the affected family. A heterozygous sister showed generalized seizures and reduction of nerve conduction velocity in her legs. No mutations were found in the epilepsy, renal failure or dilated cardiomyopathy samples. In the polyneuropathy sample two individuals with demyelinating disease were found to be carriers of a SCARB2 frameshift mutation (c.666delCCTTA).


CONCLUSIONS
Our findings indicate that demyelinating polyneuropathy and dilated cardiomyopathy are part of the action myoclonus-renal failure syndrome. Moreover, they raise the possibility that in rare cases heterozygous SCARB2 mutations may be associated with PNP features.
Institute of Human Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany. Franziska.Hopfner@gmx.de
Franziska
F
Hopfner
Barbara
B
Schormair
Franziska
F
Knauf
Achim
A
Berthele
Thomas R
TR
Tölle
Ralf
R
Baron
Christoph
C
Maier
Rolf-Detlef
RD
Treede
Andreas
A
Binder
Claudia
C
Sommer
Christian
C
Maihöfner
Wolfram
W
Kunz
Friedrich
F
Zimprich
Uwe
U
Heemann
Arne
A
Pfeufer
Michael
M
Näbauer
Stefan
S
Kääb
Barbara
B
Nowak
Christian
C
Gieger
Peter
P
Lichtner
Claudia
C
Trenkwalder
Konrad
K
Oexle
Juliane
J
Winkelmann
D000328:Adult; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics*; D004252:DNA Mutational Analysis; D003711:Demyelinating Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D051907:Lysosomal Membrane Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D051116:Receptors, Scavenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055815:Young Adult
D051907:Lysosomal Membrane Proteins; D051116:Receptors, Scavenger; C074299:SCARB2 protein, human