Two novel mutations in the GAN gene causing giant axonal neuropathy

Normendez-Martínez, Monica Irad; Monterde-Cruz, Lucero; Martínez, Roberto Valenzuela; Marquez-Harper, Magdalena; Esquitin-Garduño, Nayelli; Valdés-Flores, Margarita; Casas-Ávila, Leonora; León-Suárez, Valeria Ponce de; Romero-Díaz, Viktor J; Hidalgo‐Bravo, Alberto

doi:10.1007/s12519-018-0140-z

Cited by 14 publications

(16 citation statements)

References 24 publications

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“…(f) Progressive gait difficulties, weakness and muscular atrophy, extremely curly hair, slightly left palpebral ptosis and horizontal nystagmus, winged scapula and lumbar hyperlordosis, flaccid paraparesis, areflexia, and ataxic gait in lower limbs, positive Gower’s sign, decreased lower limbs muscle strength, patellar and plantar reflexes absent bilaterally, slight pes equinovarus deformity, axonal deterioration affecting motor and sensory function mainly of lower limbs 81 ;…”

Section: Resultsmentioning

confidence: 99%

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Chakravorty

Logan

Elson

et al. 2020

Sci Rep

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Pure sensory polyneuropathy of genetic origin is rare in childhood and hence important to document the clinical and genetic etiologies from single or multi-center studies. This study focuses on a retrospective chart-review of neurological examinations and genetic and electrodiagnostic data of confirmed sensory polyneuropathy in subjects at a tertiary-care Children’s Hospital from 2013 to 2019. Twenty subjects were identified and included. Neurological examination and electrodiagnostic testing showed gait-difficulties, absent tendon reflexes, decreased joint-position, positive Romberg’s test and large fiber sensory polyneuropathy on sensory nerve conduction studies in all patients associated with lower-extremity spasticity (6), cardiac abnormalities or cardiomyopathy (5), developmental delay (4), scoliosis (3), epilepsy (3) and hearing-difficulties (2). Confirmation of genetic diagnosis in correlation with clinical presentation was obtained in all cases (COX20 n = 2, HADHA n = 2, POLG n = 1, FXN n = 4, ATXN2 n = 3, ATM n = 3, GAN n = 2, SPG7 n = 1, ZFYVE26 n = 1, FH n = 1). Our single-center study shows genetic sensory polyneuropathies associated with progressive neurodegenerative disorders such as mitochondrial ataxia, Friedreich ataxia, spinocerebellar ataxia type 2, ataxia telangiectasia, spastic paraplegia, giant axonal neuropathy, and fumarate hydratase deficiency. We also present our cohort data in light of clinical features reported for each gene-specific disease subtype in the literature and highlight the importance of genetic testing in the relevant clinical context of electrophysiological findings of peripheral sensory polyneuropathy.

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Section: Resultsmentioning

confidence: 99%

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Chakravorty

Logan

Elson

et al. 2020

Sci Rep

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“…The lack or loss of function of gigaxonin causes giant axonal neuropathy (GAN), an autosomal recessive disorder. The GAN gene has more than 50 distinct loss of function mutations that cause the disorder (3)(4)(5)(6). The loss of both central and peripheral neurons leads to gradual muscular atrophy in this pathological condition.…”

Section: Introductionmentioning

confidence: 99%

Gigaxonin is required for intermediate filament transport

Renganathan¹,

Zewe²,

Cheng³

et al. 2022

Preprint

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Gigaxonin is an adaptor protein for E3 ubiquitin ligase substrates. It is necessary for ubiquitination and degradation of intermediate filament (IF) proteins. Giant axonal neuropathy is a pathological condition caused by mutations in the GAN gene that encodes gigaxonin. This condition is characterized by abnormal accumulation of IFs in both neuronal and non-neuronal cells; however, it is unclear what causes IF aggregation. In this work, we studied the dynamics of IFs using their subunits tagged with a photoconvertible protein mEOS 3.2. We have demonstrated that the loss of gigaxonin dramatically inhibited transport of IFs along microtubules by the microtubule motor kinesin-1. This inhibition was specific for IFs, as other kinesin-1 cargoes, with the exception of mitochondria, were transported normally. Another effect of gigaxonin loss was a more than 20-fold increase in the amount of soluble vimentin oligomers in the cytoplasm of gigaxonin knock-out cells. We speculate that these oligomers saturate a yet unidentified adapter that is required for kinesin-1 binding to IFs, which might inhibit IF transport along microtubules causing their abnormal accumulation.

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“…Giant axonal neuropathy (GAN; OMIM#256850) is a very rare autosomal recessive disorder caused by specific mutations in the GAN gene (Bomont et al, 2000). Since the first GAN report in 1972, more than 50 GAN gene mutations have been identified in 80 cases around the world (Normendez-Martinez et al, 2018). According to clinical symptoms, GAN can be divided into classical phenotype and mild phenotype; both shared the physiological features of dense nerve fiber accumulation.…”

Section: Introductionmentioning

confidence: 99%

“…Detecting GAN gene mutations is the current method used in diagnosing GAN (Normendez-Martinez et al, 2018). The GAN gene is located at 16q24.1 and encodes gigaxonin.…”

Section: Introductionmentioning

confidence: 99%

Identification of Novel Compound Heterozygous Mutations in the GAN Gene of a Chinese Patient Diagnosed With Giant Axonal Neuropathy

Yang

et al. 2020

Front. Neurosci.

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Giant axonal neuropathy (GAN) is a very rare autosomal recessive disorder characterized by abnormally large and dysfunctional neuronal axons. Mutations in the GAN gene have been identified as the cause of this disorder. In this report, we performed a detailed phenotypic assessment of a Chinese patient with GAN. An array-based exon capture test and targeted next-generation sequencing were used to detect the suspected mutation sites. Compound heterozygous mutations of p.S79L (c.236C > T) in the BTB domain and p.T489S (c.1466C > G) in the kelch domain were identified in the proband's genome. S79L was a known mutation, and T489S was reported for the first time. The p.S79L and p.T489S were confirmed in the proband's mother and father, respectively. Both mutations were located in highly conserved regions and affected the predicted protein crystal structures. The proband's sural biopsy revealed the classical GAN phenotype of swollen axons filled with closely packed neurofilaments. The combined application of the next-generation sequencing platform and bioinformatics analyses was an effective method for diagnosing GAN. The novel compound mutations of S79L and T489S in the GAN gene were likely the cause of the patient's GAN symptoms. Our findings enrich the spectrum of mutations associated with this rare type of axonopathy.

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Two novel mutations in the GAN gene causing giant axonal neuropathy

Abstract: This work provides useful information for health professionals and expands the spectrum of disease-causing mutations in the GAN gene and it is the first documented case in Mexican population.

Cited by 14 publications

References 24 publications

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Expanding the genotype–phenotype correlation of childhood sensory polyneuropathy of genetic origin

Gigaxonin is required for intermediate filament transport

Identification of Novel Compound Heterozygous Mutations in the GAN Gene of a Chinese Patient Diagnosed With Giant Axonal Neuropathy

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