This report describes spastic paraplegia 10 (SPG10), which is a subtype of spastic paraplegia; SPG10 exhibits autosomal dominant inheritance. The human gene implicated in this disease is KIF5A, a kinesin heavy chain gene. KIF5A is one of three human genes orthologous to the Drosophila gene Khc. Classical amorphic and loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis are available for Dmel\Khc.
The human KIF5A gene has not been introduced into flies.
Amorphic (null) mutations of Dmel\Khc are lethal when homozygous. SPG10 is modeled by an allele of Khc with a missense mutation that corresponds to a variant that is associated with spastic paraplegia in the human gene. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): N262S in the fly Khc gene (corresponds to N256S in the human KIF5A gene). Genetic and physical interaction(s) of the Dmel\Khc gene and protein product have been described; see below and in the gene report for Khc.
[updated Jan. 2017 by FlyBase; FBrf0222196]
The hereditary spastic paraplegias (SPG, HSP) are a large group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity and weakness. SPG is classified by mode of inheritance (autosomal dominant, autosomal recessive, and X-linked) and whether the primary symptoms occur in isolation ('uncomplicated SPG') or with other neurologic abnormalities ('complicated SPG'). [from OMIM:182600; 15.06.29]
[SPASTIC PARAPLEGIA 10, AUTOSOMAL DOMINANT; SPG10](https://omim.org/entry/604187)
[KINESIN FAMILY MEMBER 5A; KIF5A](https://omim.org/entry/602821)
Although 100% penetrant in the families studied, age of onset of SPG10 was variable, ranging from early childhood to 30 years old. It is slowly progressive and follows a rather benign course, with patients retaining the ability to walk (Schule, et al., 2008, pubmed:18245137).
See general description of spastic paraplegia above. Most cases of SPG10 meet the criteria of uncomplicated SPG, but some may involve additional neurological symptoms.
Most cases of SPG10 represent a pure form of HSP with late onset. Complex forms may occur with additional symptoms including upper limb amyotrophy, intellectual disability, hearing loss and retinitis pigmentosa. Parkinsonism, with symptoms such as tremor, abnormal slowness of movement and an inability to remain in a stable or balanced position, may also occur. Onset can range from infancy to mid-adulthood. [from NORD: Hereditary Spastic Paraplegia; 2016.09.02]
KIF5A encodes a kinesin heavy chain; kinesins are microtubule-based motor proteins involved in the transport of organelles. In neurons, kinesins are essential for intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. All initially characterized SPG10 mutations were located in the motor domain of the KIF5A protein. [from OMIM:602821; 15.06.30]
Many to one: many human to 1 Drosophila; additional human orthologous genes are KIF5B and KIF5C.
Ortholog of human genes KIF5A, KIF5B and KIF5C (1 Drosophila to many human). Dmel\Khc shares 60% identity and 76% similarity with human KIF5A; 61% identity and 77% similarity with human KIF5B; and 61% identity and 77% similarity with human KIF5C.