Variants in <i>MME</i> are associated with autosomal‐recessive distal hereditary motor neuropathy

Hong, Daojun; Pu, Fang; Yao, Sheng; Chen, Juanjuan; Zhang, Xiaolei; Chen, Shuyun; Zhang, Jingfen; Tan, Dandan; Wang, Li; Han, Xinsheng; Xin, Ling; Wang, Yan; Liu, Meige; Cong, Lu; Zhong, Shanshan; Ouyang, Hui; Gao, Xuguang; Zhang, Jun

doi:10.1002/acn3.50868

Cited by 10 publications

(11 citation statements)

References 23 publications

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“…Although the majority of dHMN patients showed an autosomal dominant inherited mode, autosomal recessive dHMNs have been associated with variants in the SORD , IGHMBP2, PLEKHG5, DNAJB2, SIGMAR1, SYT2, ATM, TBCE , and VRK1 genes 20,32 . Our study indicated that variants in the MME gene were associated with autosomal‐recessive dHMN, and as the second disease‐causing gene for genetically confirmed cases in our patient cohort.…”

Section: Discussionmentioning

confidence: 52%

“…Two unrelated individuals presented with gait disturbance and length‐dependent motor neuropathy, and had a loss‐of‐function biallelic variant (c.757delG, p.A253Qfs*27) in the SORD (NM_003104) gene. 19 Four dHMN patients from three families were associated with loss‐of‐function variants in the MME (NM_000902) gene, of which three patients have been described in our previous report, 20 and the last showed chronic progressive weakness and wasting of distal limbs. A novel c.3854A>C (p.K1285T) variant in the ATP7A (NM_000052) gene was associated with early‐onset dHMN patient with initial involvement of upper limb.…”

Section: Resultsmentioning

confidence: 96%

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Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

Xiang

Chen

et al. 2022

Ann Clin Transl Neurol

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Background Distal hereditary motor neuropathy (dHMN) is a heterogeneous group of diseases characterized by exclusive degeneration of peripheral motor nerves, while only 20.0–47.8% of dHMN patients are genetically identified. Recently, GGC expansion in the 5’UTR of NOTCH2NLC has been associated with dHMN. Accordingly, short tandem repeat (STR) should be further explored in genetically unsolved patients with dHMN. Methods A total of 128 patients from 90 unrelated families were clinically diagnosed as dHMN, and underwent a comprehensively genetic screening. Skin biopsies were conducted with routine protocols. Results Most patients showed chronic distal weakness of lower limbs (121/128), while 20 patients initially had asymmetrical involvements, 14 had subclinical sensory abnormalities, 11 had pyramidal impairments, five had cerebellar disturbance, and four had hyperCKmia. The rate of genetic detection was achieved in 36.7% (33/90), and the rate increased to 46.7% (42/90) if patients with variants uncertain significance were included. The most common causative genes included chaperone‐related genes (8/33, 24.2%), tRNA synthetase genes (4/33, 12.1%), and cytoskeleton‐related genes (4/33, 12.1%). Additionally, two dominant inherited families were attributed to abnormal expansion of GGC repeats in the 5‘UTR of NOTCH2NLC; and a patient with dHMN and cerebellar symptoms had CAG repeat expansion in the ATXN2 gene. Skin biopsy from patients with GGC expansion in NOTCH2NLC revealed typical intranuclear inclusions on histological and ultrastructural examinations. Interpretations This study further extends the genetic heterogeneity of dHMN. Given some dHMN patients may be associated with nucleotides repeat expansion, STR screening is necessary to perform in genetically unsolved patients.

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Section: Discussionmentioning

confidence: 52%

Section: Resultsmentioning

confidence: 96%

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

Xiang

Chen

et al. 2022

Ann Clin Transl Neurol

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“…However, in three cases, disease onset was before age 35 years. Moreover, we ascertained five patients with predominant motor involvement or pyramidal tract signs, leading to a diagnosis of dHMN in one family (similar to previously reported cases 43 ) and ALS in three families.…”

Section: A C C E P T E Dmentioning

confidence: 70%

The genetic landscape of axonal neuropathies in the middle-aged and elderly

Senderek¹,

Laššuthová²,

Kabzińska³

et al. 2020

Neurology

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ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.MethodsWe recruited patients, collected clinical data and conducted whole-exome sequencing (WES, n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin.ResultsIn the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal dominant trait and less frequently with autosomal recessive inheritance.ConclusionsA detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, either by variants in CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.

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“…Interestingly, two homozygous mutations c.1342C>T (p.Arg448*) and c.1861T>C (p.Cys621Arg) detected in MME were associated to CMT2 in two unrelated Iranian families, both of which were predicted to be pathogenic based on in silico analysis. Interestingly, p.Arg448* was also detected in homozygous status in Spanish patients diagnosed with late‐onset axonal CMT (Lupo et al, 2018 ) and in compound heterozygote in Chinese patients with distal hereditary motor neuropathy (Hong et al, 2019 ). While in the study by Auer‐Grumbach et al ( 2016 ) this mutation was associated with late‐onset autosomal dominant polyneuropathies.…”

Section: Discussionmentioning

confidence: 97%

“…The genetic causes of more than 90% of CMT cases are due to mutations in four genes including PMP22 , GJB1 , MFN2 , and MPZ (Auer‐Grumbach et al, 2003 ; Chung, 2006 ; Nave et al, 2007 ; Timmerman et al, 2014 ), with PMP22 mutations alone accounting for ~70% of CMT1 cases while in CMT2, mutations in GJB1 and MFN2 are more frequent (Azzedine et al, 2012 ). The MME gene (OMIM #120520) is among frequently mutated genes in patients with late‐onset axonal form of CMT (Auer‐Grumbach et al, 2016 ; Higuchi et al, 2016 ; Hong et al, 2019 ; Lupo et al, 2018 ; Senderek et al, 2020 ; Taghizadeh et al, 2020 ). MME mutations have been shown to associate to both dominant and recessive CMT2.…”

Section: Introductionmentioning

confidence: 99%

A nonsense mutation inMMEgene associates with autosomal recessive late‐onsetCharcot–Marie–Toothdisease

Jamiri

Khosravi

Heidari

et al. 2022

Molec Gen & Gen Med

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Background The genetic cause for the majority of patients with late‐onset axonal form of neuropathies have remained unknown. In this study we aimed to identify the causal mutation in a family with multiple affected individuals manifesting a range of phenotypic features consistent with late‐onset sensorimotor axonal polyneuropathy. Methods Whole exome sequencing (WES) followed by targeted variant screening and prioritization was performed to identify the candidate mutation. The co‐segregation of the mutation with the phenotype was confirmed by Sanger sequencing. Results We identified a nonsense mutation (c.1564C>T; p.Q522*) in membrane metalloendopeptidase ( MME ) gene as the cause of the disease condition. The mutation has a combined annotation‐ dependent depletion (CADD) score 45 and predicted to be deleterious based on various algorithms. The mutation was inherited in an autosomal recessive mode and further confirmed to co‐segregate with the disease phenotype in the family and showed to has the required criteria including rarity and deleteriousness to be considered as pathogenic. Conclusion The MME gene encodes for the membrane bound endopeptidase neprilysin (NEP) which is involved in processing of various peptide substrates. The identified mutation causes a complete loss of carboxy‐terminal region of the NEP protein which contains the zinc binding site and the catalytic domain and thus considered to be a loss‐of‐function mutation. The loss of NEP activity is likely associated with impaired myelination and axonal injury which is hallmark of CMT diseases.

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Variants in MME are associated with autosomal‐recessive distal hereditary motor neuropathy

Cited by 10 publications

References 23 publications

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy

The genetic landscape of axonal neuropathies in the middle-aged and elderly

A nonsense mutation inMMEgene associates with autosomal recessive late‐onsetCharcot–Marie–Toothdisease

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