Spinal muscular atrophy with pontocerebellar hypoplasia is caused by a mutation in the VRK1 gene.
The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to muscle weakness and atrophy. Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA variants that include additional clinical manifestations, and its genetic basis is unknown. We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one of three members of the mammalian VRK family, is a serine/threonine kinase that phosphorylates p53 and CREB and is essential for nuclear envelope formation. Its identification as a gene involved in SMA-PCH implies new roles for the VRK proteins in neuronal development and maintenance and suggests the VRK genes as candidates for related phenotypes.
Renbaum
Paul
P
Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel.
Kellerman
Efrat
E
Jaron
Ranit
R
Geiger
Dan
D
Segel
Reeval
R
Lee
Ming
M
King
Mary Claire
MC
Levy-Lahad
Ephrat
E
D000483:Alleles; D001927:Brain Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14; D003001:Cloning, Molecular; D018389:Codon, Nonsense; D003241:Consanguinity; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007557:Israel; D007585:Jews; D008126:Lod Score; D008297:Male; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D020161:Physical Chromosome Mapping; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D014463:Ultrasonography
D018389:Codon, Nonsense; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C109890:VRK1 protein, human