KIF1C mutations in two families with hereditary spastic paraparesis and cerebellar dysfunction.
J Med Genet. 2013-12-06; 51(2): 137-142
DOI: 10.1136/jmedgenet-2013-102012
Lire sur PubMed
1. J Med Genet. 2014 Feb;51(2):137-42. doi: 10.1136/jmedgenet-2013-102012. Epub 2013
Dec 6.
KIF1C mutations in two families with hereditary spastic paraparesis and
cerebellar dysfunction.
Dor T(1), Cinnamon Y, Raymond L, Shaag A, Bouslam N, Bouhouche A, Gaussen M,
Meyer V, Durr A, Brice A, Benomar A, Stevanin G, Schuelke M, Edvardson S.
Author information:
(1)Department of Pediatrics, Neuropediatric Unit, Hadassah-Hebrew University
Medical Center, Jerusalem, Israel.
BACKGROUND: Hereditary spastic paraparesis (HSP) (syn. Hereditary spastic
paraplegia, SPG) are a group of genetic disorders characterised by spasticity of
the lower limbs due to pyramidal tract dysfunction. Nearly 60 disease loci have
been identified, which include mutations in two genes (KIF5A and KIF1A) that
encode motor proteins of the kinesin superfamily. Here we report a novel genetic
defect in KIF1C of patients with spastic paraparesis and cerebellar dysfunction
in two consanguineous families of Palestinian and Moroccan ancestry.
METHODS AND RESULTS: We performed autozygosity mapping in a Palestinian and
classic linkage analysis in a Moroccan family and found a locus on chromosome 17
that had previously been associated with spastic ataxia type 2 (SPAX2, OMIM
%611302). Whole-exome sequencing revealed two homozygous mutations in KIF1C that
were absent among controls: a nonsense mutation (c.2191C>T, p.Arg731*) that
segregated with the disease phenotype in the Palestinian kindred resulted in the
entire absence of KIF1C protein from the patient’s fibroblasts, and a missense
variant (c.505C>T, p.Arg169Trp) affecting a conserved amino acid of the motor
domain that was found in the Moroccan kindred.
CONCLUSIONS: Kinesin genes encode a family of cargo/motor proteins and are known
to cause HSP if mutated. Here we identified nonsense and missense mutations in a
further member of this protein family. The KIF1C mutation is associated with a
HSP subtype (SPAX2/SAX2) that combines spastic paraplegia and weakness with
cerebellar dysfunction.
DOI: 10.1136/jmedgenet-2013-102012
PMID: 24319291 [Indexed for MEDLINE]