Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy

AbstractSorbitol dehydrogenase gene (SORD) has been identified as a novel causative gene of recessive forms of hereditary neuropathy, including Charcot–Marie–Tooth disease type 2 and distal hereditary motor neuropathy (dHMN). Our findings reveal two novel variants (c.404 A > G and c.908 + 1 G > C) and one known variant (c.757delG) within SORD in four Chinese dHMN families. Ex vivo cDNA polymerase chain reaction confirmed that c.908 + 1 G > C variant was associated with impaired splicing of the SORD transcript. In vitro cell functional studies showed that c.404 A > G variant resulted in aggregate formation of SORD and low protein solubility, confirming the pathogenicity of SORD variants. We have provided more evidence to establish SORD as a causative gene for dHMN.

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Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy

Frontiers in Neurology ◽

10.3389/fneur.2021.733926 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoxuan Liu ◽

Ji He ◽

Mubalake Yilihamu ◽

Xiaohui Duan ◽

Dongsheng Fan

Keyword(s):

Chinese Patients ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Charcot Marie Tooth ◽

Hereditary Motor ◽

Whole Exome ◽

Hereditary Motor Neuropathy ◽

Genetic Features ◽

Chinese Cohort ◽

Biallelic Mutations

Biallelic mutations in the sorbitol dehydrogenase (SORD) gene have recently been found to be one of the most frequent causes of autosomal recessive axonal Charcot-Marie-Tooth (CMT2) and distal hereditary motor neuropathy (dHMN). This study was performed to explore the frequency of SORD mutations and correlations of the phenotypic-genetic spectrum in a relatively large Chinese cohort. In this study, we screened a cohort of 485 unrelated Chinese patients with hereditary neuropathy by using Sanger sequencing, next generation sequencing, or whole exome sequencing after PMP22 duplication was initially excluded. SORD mutation was identified in five out of 78 undiagnosed patients. Two individuals carried the previously reported homozygous c.757 delG (p.A253Qfs*27) variant, and three individuals carried the heterozygous c.757delG (p.A253Qfs*27) variant together with a second novel likely pathogenic variant, including c.731 C>T (p.P244L), c.776 C>T (p.A259V), or c.851T>C (p.L284P). The frequency of SORD variants was calculated to be 6.4% (5/78) in unclarified CMT2 and dHMN patients. All patients presented with distal weakness and atrophy in the lower limb, two of whom had minor clinical sensory abnormalities and small fiber neuropathy. Our study provides further information on the genotype and phenotype of patients with SORD mutations.

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Chinese patients with distal hereditary motor neuropathy: an analysis of clinical characteristics

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2009.00057 ◽

2010 ◽

Vol 29 (1) ◽

pp. 57-60

Author(s):

Fu-feng ZHANG ◽

Xiao-qin LU ◽

Xin-xiang YAN ◽

Min FU ◽

Peng GUO ◽

...

Keyword(s):

Clinical Characteristics ◽

Chinese Patients ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy

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Glycyl tRNA Synthetase (GARS) Gene Variant Causes Distal Hereditary Motor Neuropathy V

Case Reports in Pediatrics ◽

10.1155/2018/8516285 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4 ◽

Cited By ~ 3

Author(s):

Peter Chung ◽

Hope Northrup ◽

Misbah Azmath ◽

Ricardo A. Mosquera ◽

Shade Moody ◽

...

Keyword(s):

Muscular Atrophy ◽

Trna Synthetase ◽

Motor Neuropathy ◽

Inherited Disorders ◽

Causative Gene ◽

Hereditary Motor ◽

Pathogenic Variants ◽

Neurogenic Muscular Atrophy ◽

Hereditary Motor Neuropathy ◽

Type V

Distal hereditary motor neuropathies (dHMN) are a rare heterogeneous group of inherited disorders specifically affecting the motor axons, leading to distal limb neurogenic muscular atrophy. The GARS gene has been identified as a causative gene responsible for clinical features of dHMN type V in families from different ethnic origins and backgrounds. We present the first cohort of family members of Nigerian descent with a novel heterozygous p.L272R variant on the GARS gene. We postulate that this variant is the cause of dHMN-V in this family, leading to variable phenotypical expressions that are earlier than reported in previous cases. The exact cause for the observed clinical heterogeneity within the family is unknown. One explanation is that there are modifier genes that affect the phenotype. These cases highlight the possibility of considering pathogenic variants in the GARS gene as a potential cause of early onset axonal polyneuropathy with atypical presentation.

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167 An in-vitro study of distal hereditary motor neuropathy due to homozygous HSJ1 mutations

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2011-301993.209 ◽

2012 ◽

Vol 83 (3) ◽

pp. e1.123-e1

Author(s):

A Rossor ◽

B Kalmar ◽

A Gray ◽

W Mustill ◽

G Schiavo ◽

...

Keyword(s):

In Vitro Study ◽

Vitro Study ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy

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Faculty Opinions recommendation of Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.2526956.9237054 ◽

2011 ◽

Author(s):

Davide Pareyson ◽

Chiara Marchesi

Keyword(s):

Motor Neuropathy ◽

Missense Mutations ◽

Transporter Gene ◽

Copper Transporter ◽

Hereditary Motor ◽

Hereditary Motor Neuropathy

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Effect of Processing on Fish Protein Antigenicity and Allergenicity

Foods ◽

10.3390/foods10050969 ◽

2021 ◽

Vol 10 (5) ◽

pp. 969

Author(s):

Xingyi Jiang ◽

Qinchun Rao

Keyword(s):

Fish Species ◽

Protein Denaturation ◽

Ex Vivo ◽

Protein Solubility ◽

Future Research ◽

Food Protein ◽

In Vivo Evaluation ◽

Fish Allergy

Fish allergy is a life-long food allergy whose prevalence is affected by many demographic factors. Currently, there is no cure for fish allergy, which can only be managed by strict avoidance of fish in the diet. According to the WHO/IUIS Allergen Nomenclature Sub-Committee, 12 fish proteins are recognized as allergens. Different processing (thermal and non-thermal) techniques are applied to fish and fishery products to reduce microorganisms, extend shelf life, and alter organoleptic/nutritional properties. In this concise review, the development of a consistent terminology for studying food protein immunogenicity, antigenicity, and allergenicity is proposed. It also summarizes that food processing may lead to a decrease, no change, or even increase in fish antigenicity and allergenicity due to the change of protein solubility, protein denaturation, and the modification of linear or conformational epitopes. Recent studies investigated the effect of processing on fish antigenicity/allergenicity and were mainly conducted on commonly consumed fish species and major fish allergens using in vitro methods. Future research areas such as novel fish species/allergens and ex vivo/in vivo evaluation methods would convey a comprehensive view of the relationship between processing and fish allergy.

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Distal hereditary motor neuropathy (DHMN): a new locus for an autosomal recessive form

Journal of the Peripheral Nervous System ◽

10.1111/j.1085-9489.2004.009209bi.x ◽

2004 ◽

Vol 9 (2) ◽

pp. 122-123 ◽

Cited By ~ 2

Author(s):

ML Mostacciuolo ◽

E Crestanello ◽

F Boaretto ◽

E Boscolo ◽

M Liguori ◽

...

Keyword(s):

Autosomal Recessive ◽

Motor Neuropathy ◽

Hereditary Motor ◽

Autosomal Recessive Form ◽

Recessive Form ◽

Hereditary Motor Neuropathy

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Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105650 ◽

2018 ◽

Vol 55 (12) ◽

pp. 814-823 ◽

Cited By ~ 8

Author(s):

Vincenzo Lupo ◽

Marina Frasquet ◽

Ana Sánchez-Monteagudo ◽

Ana Lara Pelayo-Negro ◽

Tania García-Sobrino ◽

...

Keyword(s):

Autosomal Recessive ◽

Late Onset ◽

Axonal Neuropathy ◽

Genetic Diagnosis ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Charcot Marie Tooth Disease ◽

Hereditary Motor Neuropathy ◽

Index Cases ◽

Mode Of Inheritance

BackgroundMutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.MethodsWe screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.ResultsWe found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.ConclusionMME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

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