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Metabolic and biophysical study of the MFN2Ile213Thr mutant causing Hereditary Motor and Sensory Neuropathy (HMSN)

ABSTRACT: Charcot-Marie-Tooth (CMT) 2A disease, a genetic axonal nervous lesion, results from MFN2 pathogenic variation, and this gene plays a pivotal role in mitochondrial dynamics and calcium signaling. However, the underlying mechanism linking MFN2 defect to progressive dying-back of peripheral nerves is still unclear. The present work focused on analyzing one CMT2A patient from multiple perspectives. Clinical and pathologic evaluation was initially conducted on the recruited case. Subsequently, Sanger sequencing and whole-exome sequencing (WES) were performed for genetic detection. To reveal the cell metabolic alteration caused by the identified variant, this study also established and transfected plasmid vectors in HEK293 cells and analyzed cell metabolites through liquid chromatography in combination with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS). Additionally, we completed structural modeling and molecular dynamic (MD) simulation to investigate the intramolecular impact of the variant. According to our results, the clinical and neuropathologic manifestations of the proband matched with the diagnosis of CMT. The causative variant MFN2: c.638T>C: (p.Ile213Thr) was identified through genetic analysis. Moreover, metabolic pathway enrichment results demonstrated that this variant significantly affected the metabolism of sphingolipids and glycerophospholipids. MD analysis indicated that this variant crippled the binding ability of MFN2 to GTP. Taken together, our study deduced preliminary clues for the underlying mechanism by which mutant MFN2 affects cell metabolism and provided a novel perspective to understand the cellular and molecular impacts of MFN2 variants.

SUBMITTER: Yang K

PROVIDER: S-EPMC8581889 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin tumours like amelanotic melanoma. Management of HSN I follows the guidelines given for diabetic foot care (removal of pressure to the ulcer and eradication of infection, followed by the use of specific protective footwear) and starts with early and accurate counselling of patients about risk factors for developing foot ulcerations. The disorder is slowly progressive and does not influence life expectancy but is often severely disabling after a long duration of the disease.

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Metabolic and biophysical study of the MFN2Ile213Thr mutant causing Hereditary Motor and Sensory Neuropathy (HMSN)

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