KIF1A missense mutations in SPG30, an autosomal recessive spastic paraplegia: distinct phenotypes according to the nature of the mutations

Abstract

The hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. The nosology of autosomal recessive forms is complex as most mapped loci have been identified in only one or a few families and account for only a small percentage of patients. We used next-generation sequencing focused on the SPG30 chromosomal region on chromosome 2q37.3 in two patients from the original linked family. In addition, wide genome scan and candidate gene analysis were performed in a second family of Palestinian origin. We identified a single homozygous mutation, p.R350G, that was found to cosegregate with the disease in the SPG30 kindred and was absent in 970 control chromosomes while affecting a strongly conserved amino acid at the end of the motor domain of KIF1A. Homozygosity and linkage mapping followed by mutation screening of KIF1A allowed us to identify a second mutation, p.A255V, in the second family. Comparison of the clinical features with the nature of the mutations of all reported KIF1A families, including those reported recently with hereditary sensory and autonomic neuropathy, suggests phenotypegenotype correlations that may help to understand the mechanisms involved in motor neuron degeneration. We have shown that mutations in the KIF1A gene are responsible for SPG30 in two autosomal recessive HSP families. In published families, the nature of the KIF1A mutations seems to be of good predictor of the underlying phenotype and vice versa. INTRODUCTIONThe hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases characterised by progressive spasticity in the lower limbs. 1 The mode of inheritance may be autosomal dominant, autosomal recessive (ARHSP) or X-linked. More than 48 different loci (SPGn) have been mapped so far, and 23 responsible genes identified. The corresponding proteins are often involved in intracellular trafficking or mitochondrial functions. 2,3 Clinically, one can distinguish between pure and complicated forms of HSP. 1,2 Pure forms consist of isolated pyramidal signs, such as spasticity, abnormal reflexes (brisk reflexes and Babinski sign) and motor deficit, often associated with sphincter disturbances and deep sensory loss. In the complicated forms of HSP the disease is variably associated with numerous combinations of neurological and extraneurological signs, such as cerebellar ataxia, dysarthria, mental retardation, peripheral neuropathy, optic atrophy, retinitis pigmentosa and/or hearing loss, which may be accompanied by abnormal brain MRI (atrophy of the cortex, cerebellum or corpus callosum, white matter abnormalities, etc).Mutations in the KIF1A gene (MIM 601255) were very recently described in two different clinically and genetically heterogeneous groups of neurodegenerative diseases. 4,5 In hereditary sensory and autonomic neuropathy (HSAN), all patients from four families with different origins shared a common hom...

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

“…10 On the basis of structural analyses, the recessive variants c.764C4T (p. (Ala255Val)) and c.1048C4G (p.(Arg350Gly)) were predicted to disrupt the back door structure or the neck linker between the motor domain and cargo binding regions, respectively. 6,7,10 Functional testing by the expression of variants in rat hippocampal neurons suggested that the recessive variants impaired motor activity of KIF1A but to a lesser degree than the dominant disease variants. 10 Therefore, a less severe biochemical phenotype may explain why c.764C4T (p.(Ala255Val)) and c.1048C4G (p.(Arg350Gly)) are disease causing only in the homozygous state.…”

“…5 Next, homozygous missense variants in the KIF1A motor domain were found causative for the autosomal recessive hereditary spastic paraplegia (HSP) subtype SPG30. [6][7][8] HSP is characterized by the degeneration of axons of the corticospinal tract motor neurons. If additional symptoms or signs are present, the patient has 'complicated' rather than 'pure' HSP.…”

Delineation of C12orf65-related phenotypes: a genotype–phenotype relationship

“…5 In family B, total RNA was isolated from peripheral blood lymphocytes and reverse transcribed to cDNA. The cDNA obtained was PCR-amplified using forward and reverse primers corresponding to cDNA positions c.124 and c.738 (NM_001143905.2) in exon 1 and exon 3, respectively.…”

Clinical and genetic heterogeneity in hereditary spastic paraplegias: From SPG1 to SPG72 and still counting

“…SPG30 is a rare ARHSP form with an age at onset between 10 and 39 years and a slow disease progression 84,85 . Cerebellar signs, or cerebellar atrophy and axonal sensorimotor peripheral neuropathy are frequently associated signs.…”