Objective: To identify a genetic cause for hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V).

Background: Hereditary spastic paraplegia (HSP) constitutes a heterogeneous group of neurodegenerative disease characterized by the axonal degeneration of the longest descending (pyramidal) tracts. Clinically, HSP can overlap with other motor neuron diseases such as Charcot-Marie-Tooth (CMT) disease and ALS (amyotrophic lateral sclerosis). To date, genetic defect remains to be elucidated in approximately 20% case of HSP and 50% case of sporadic spastic paraplegia. Further identification of genetic defects in HSP would justify therapeutic strategies.

Methods: We performed a clinico-genetical study in a Japanese family, in which two sibships are affected with HMSN type V, including whole exome sequencing, bioinformatic analyses, pathological and ultrastructural study of biopsied nerve. Expression level of DNAJA3 was evaluated using quantitative PCR in Rat neuronal tissues. Biological effect of homozygous variant, p.Y95H in DNAJA3 gene, was evaluated by cell viability study in cultured cells. Suppression of endogenous Drosophila DNAJA3 using RNAi was also performed to evaluate its effects on motoneurons terminal synapsis and locomotive behaviour.

Results: Electrophysiological investigation revealed axonal degeneration in peripheral sensory and motor neurons. Electron microscopic examination demonstrated abnormal mitochondrial morphology in the biopsied sural nerve. Genetic analyses demonstrated a novel homozygous variant, p.Y95H, in DNAJA3 gene. The variant was not found in 618 control chromosomes recruited in Japan and Italy, and is predicted to be damaging/deleterious or disease causing. Higher level of DNAJA3 was also present in the nervous system, especially anterior horn, and lower level in hippocampus. Decreased viability in the cells expressing mutant DNAJA3 was demonstrated under the conditioning of rotenone-induced oxidative stress. Reduced expression of DNAJA3 showed reduced locomotor activity in Drosophila melanogaster.

Conclusions: A novel homozygous missense mutation, c.283T>C (p.Y95H), in DNAJA3 was identified in single family with hereditary motor and sensory neuropathy with spastic paraplegia (HMSN type V). The mutation would result in impairment of mitochondrial biogenesis leading to disruption of axonal maintenance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-homozygous-loss-of-function-mutation-in-dnaja3-causes-hereditary-motor-and-sensory-neuropathy-with-spastic-paraplegia-hmsn-type-v/