Novel pathogenic LRRK2 p.Asn1437His substitution in familial Parkinson's disease.
Genealogical investigation of a large Norwegian family (F04) with autosomal dominant parkinsonism has identified 18 affected family members over four generations. Genetic studies have revealed a novel pathogenic LRRK2 mutation c.4309 A>C (p.Asn1437His) that co-segregates with disease manifestation (LOD = 3.15, θ = 0). Affected carriers have an early age at onset (48 ± 7.7 SD years) and are clinically asymmetric and levodopa responsive. The variant was absent in 623 Norwegian control subjects. Further screening of patients from the same population identified one additional affected carrier (1 of 692) with familial parkinsonism who shares the same haplotype. The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.
Aasly
Jan O
JO
Department of Neurology, St. Olav's Hospital, Trondheim, Norway.
Vilariño-Güell
Carles
C
Dachsel
Justus C
JC
Webber
Philip J
PJ
West
Andrew B
AB
Haugarvoll
Kristoffer
K
Johansen
Krisztina K
KK
Toft
Mathias
M
Nutt
John G
JG
Payami
Haydeh
H
Kachergus
Jennifer M
JM
Lincoln
Sarah J
SJ
Felic
Amela
A
Wider
Christian
C
Soto-Ortolaza
Alexandra I
AI
Cobb
Stephanie A
SA
White
Linda R
LR
Ross
Owen A
OA
Farrer
Matthew J
MJ
D000368:Aged; D000369:Aged, 80 and over; D001216:Asparagine / Q000235:genetics*; D002461:Cell Line, Transformed; D005260:Female; D005820:Genetic Testing; D006160:Guanosine Triphosphate / Q000378:metabolism; D006639:Histidine / Q000235:genetics*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009664:Norway; D010300:Parkinson Disease / Q000175:diagnosis / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011569:Psychiatric Status Rating Scales; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014162:Transfection / Q000379:methods
D006639:Histidine; D001216:Asparagine; D006160:Guanosine Triphosphate; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases