Novel mutations consolidate KCTD7 as a progressive myoclonus epilepsy gene.
BACKGROUND
The progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous disorders characterised by myoclonus, epilepsy, and neurological deterioration. This study aimed to identify the underlying gene(s) in childhood onset PME patients with unknown molecular genetic background.


METHODS
Homozygosity mapping was applied on genome-wide single nucleotide polymorphism data of 18 Turkish patients. The potassium channel tetramerisation domain-containing 7 (KCTD7) gene, previously associated with PME in a single inbred family, was screened for mutations. The spatiotemporal expression of KCTD7 was assessed in cellular cultures and mouse brain tissue.


RESULTS
Overlapping homozygosity in 8/18 patients defined a 1.5 Mb segment on 7q11.21 as the major candidate locus. Screening of the positional candidate gene KCTD7 revealed homozygous missense mutations in two of the eight cases. Screening of KCTD7 in a further 132 PME patients revealed four additional mutations (two missense, one in-frame deletion, and one frameshift-causing) in five families. Eight patients presented with myoclonus and epilepsy and one with ataxia, the mean age of onset being 19 months. Within 2 years after onset, progressive loss of mental and motor skills ensued leading to severe dementia and motor handicap. KCTD7 showed cytosolic localisation and predominant neuronal expression, with widespread expression throughout the brain. None of three polypeptides carrying patient missense mutations affected the subcellular distribution of KCTD7.


CONCLUSIONS
These data confirm the causality of KCTD7 defects in PME, and imply that KCTD7 mutation screening should be considered in PME patients with onset around 2 years of age followed by rapid mental and motor deterioration.
Folkhälsan Institute of Genetics, Biomedicum Helsinki, PO Box 63, Haartmaninkatu 8, University of Helsinki, FIN-00014 Helsinki, Finland.
Maria
M
Kousi
Verneri
V
Anttila
Angela
A
Schulz
Stella
S
Calafato
Eveliina
E
Jakkula
Erik
E
Riesch
Liisa
L
Myllykangas
Hannu
H
Kalimo
Meral
M
Topçu
Sarenur
S
Gökben
Fusun
F
Alehan
Johannes R
JR
Lemke
Michael
M
Alber
Aarno
A
Palotie
Outi
O
Kopra
Anna-Elina
AE
Lehesjoki
D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D002478:Cells, Cultured; D002874:Chromosome Mapping; D006720:Homozygote; D006801:Humans; D042541:Intracellular Space; D051379:Mice; D008856:Microscopy, Fluorescence; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015221:Potassium Channels / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014421:Turkey
C522280:KCTD7 protein, human; D015221:Potassium Channels