De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy

Abstract

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia

“…Heterozygous KIF1A variants had not been described in HSP phenotypes until a recent report by us and collaborators where 11 de novo variants were described in 14 patients. 10 The predominant phenotype in these cases was developmental delay and/or ID with cerebellar, cerebral and/or optic nerve atrophy. Spasticity was present in most but not all patients.…”

“…9 The phenotypic spectrum of KIF1A-related disease grew recently further with the identification of de novo missense variants in the motor domain in patients who had intellectual disability (ID) in addition to variable other symptoms including spastic paraparesis, axonal neuropathy and cerebellar atrophy. [10][11][12] Here we report the first dominantly inherited KIF1A variant, which caused pure HSP.…”

Multigeneration family with dominant SPG30 hereditary spastic paraplegia

“…Intriguingly, most of these cases differ substantially from typical presentations of patients with heterozygous missense mutations in the motor domain, as these patients typically have a far more severe phenotype with prominent cognitive impairment and other associated neurologic findings 3, 4, 5, 16. Perhaps, the fact that Ser69 is not invariant and occurs within a small segment of the motor domain that appears relatively divergent (Fig.…”

“…Given this crucial role in cellular transport, it is not surprising that alterations in KIFs have been implicated in a variety of inherited disorders, particularly affecting the nervous system. For instance, mutations in the gene encoding the brain‐specific kinesin KIF1A – involved in anterograde axonal transport and learning enhancement2 – lead to a variety of neurological syndromes, including hereditary sensory neuropathy (HSN2C, OMIM 614213), intellectual disability (MRD9, OMIM 614255), and hereditary spastic paraplegia (HSP) (SPG30, OMIM 610357) 3…”

“…Patients presenting with cognitive impairment often exhibit a relatively severe phenotype with a range of additional symptoms including optic atrophy, cerebellar ataxia, and neuropathy; they frequently carry heterozygous missense mutations in the motor domain, suggestive of a dominant‐negative pathogenic mode of action 3, 4, 5. Several different families presenting with neuropathy alone, characterized by common features of profound sensory loss and ulcero‐mutilation, have harbored recessive truncating mutations in the alternatively spliced exon 25b 6…”