De novo and dominant mutations in the kinesin gene KIF1A are a common cause of HSP.
Researchers at Radboud University in Nijmegen, Holland, identify heterozygous KIF1A variants in 6-7% of cases with HSP. Thus, KIF1A mutations are a common cause of sporadic and autosomal dominant HSP.
Variants in the KIF1A gene cause autosomal recessive HSP type SPG30 and autosomal recessive sensory neuropathy. De novo variants in the KIF1A gene have been associated with autosomal dominant mental retardation type 9. More recently, variants in KIF1A have also been described in autosomal dominant HSP cases. The team led by Erik-Jan Kamsteeg from Radboud University in Nijmegen, Holland, describes 20 KIF1A variants in 24 HSP patients. Most KIF1A mutation carriers suffered from a so-called 'pure' HSP with very variable age at disease onset (0-57 years). Segregation analyses showed a de novo occurrence of KIF1A variants in seven cases and a dominant inheritance pattern in 11 families.
The motor domain of KIF1A is a hotspot for pathogenic variants of HSP. However, variants outside this domain were also identified in six families; however, careful functional characterization is required to demonstrate their pathogenicity.
In total, KIF1A variants were identified in 6-7% of HSP patients; thus, KIF1A-associated HSP belongs to the common subtypes of autosomal dominant HSP.
Reference: Pennings M, Schouten MI, van Gaalen J, Meijer RPP, de Bot ST, Kriek M, Saris CGJ, van den Berg LH, van Es MA, Zuidgeest DMH, Elting MW, van de Kamp JM, van Spaendonck-Zwarts KY, Die-Smulders C, Brilstra EH, Verschuuren CC, de Vries BBA, Bruijn J, Sofou K, Duijkers FA, Jaeger B, Schieving JH, van de Warrenburg BP, Kamsteeg EJ. KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia. Eur J Hum Genet. 2019.