Novel mutations in HINT1 gene cause the autosomal recessive axonal neuropathy with neuromyotonia

Wang, Zhangyang; Lin, Jie; Qiao, Kai; Cai, Shuang; Zhang, Victor W.; Zhao, Chongbo; Lu, Jiahong

doi:10.1016/j.ejmg.2018.07.009

Cited by 22 publications

(19 citation statements)

References 18 publications

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“…However, because it is a very rare condition, neuromyotonia is not always easily identified (Peeters et al, 2017). Needle electromyography may help disclose neuromyotonia and distinguish NMAN from myotonic dystrophy and channelopathies causing non-dystrophic myotonia (Jerath et al, 2015;Peeters et al, 2017;Wang et al, 2019) and thus narrow the molecular diagnosis. The disease presentation of our patient was similar to other reports of HINT1 neuropathy (Jerath et al, 2015;Rauchenzauner et al, 2016;Veltsista & Chroni, 2016).…”

Section: Discussionmentioning

confidence: 99%

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report

Madeiro

Peeters

Lima

et al. 2021

Molec Gen & Gen Med

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Section: Discussionmentioning

confidence: 99%

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report

Madeiro

Peeters

Lima

et al. 2021

Molec Gen & Gen Med

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“…At the time we performed this study, the number of HINT1 mutants reported to cause ARAN-NM in humans was 15 (34, 40, 62). Thus, we addressed the capacity of these mutants to remove SUMO from sumoylated RGSZ2 and whether this activity was regulated by NO or Ca 2+ -CaM.…”

Section: Resultsmentioning

confidence: 99%

“…The columns describing isopeptidase activity and its regulation: N and Y indicate No and Yes, respectively; Y < WT denotes deregulated isopeptidase activity worse than that of the WT. Ref: references reporting the human HINT1 mutants: a (34); b (40); c (62). The assays were performed at least twice, and each point was duplicated.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, interest in this protein has increased considerably because an initial report described a series of human HINT1 mutants as the cause of the devastating condition autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) (73). Actually, 15 HINT1 mutants have been implicated in the pathophysiology of this neural dysfunction (34, 40, 62). Evidently, the identification of HINT1 features, which may be altered in these human mutants, is of outstanding interest.…”

Section: Introductionmentioning

confidence: 99%

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The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease

Cortés-Montero

Rodríguez-Muñoz

Sánchez‐Blázquez

et al. 2019

Antioxidants & Redox Signaling

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Aims: Histidine triad nucleotide-binding protein 1 (HINT1) exhibits proapoptotic and tumor-suppressive activity. HINT1 binds to transcription factors such as teneurin1 and to the regulator of G protein signaling 17 (RGS) (Z2) protein, which incorporates the small ubiquitin-like modifier (SUMO), and is implicated in several types of cancer. HINT1 interacts with proteins such as PKCγ and Raf-1 through zinc ions provided by the cysteine-rich domain of RGSZ2 and the coupled neural nitric oxide synthase (nNOS). Recently, a series of HINT1 mutants have been reported to cause human autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM). However, the specific alteration in the function of HINT1 induced by these mutants remains to be elucidated. Because sumoylation modifies protein association and transcriptional regulation, we investigated whether HINT1 exhibits zinc- and redox-regulated sumoylase activity, which may be altered in those mutants. Results: HINT1 exhibits cysteine protease activity to remove SUMO from a variety of signaling proteins. HINT1 sumoylase activity is blocked by zinc, and it is released by nitric oxide or calcium-activated calmodulin (CaM). HINT1 contains a SUMO-interacting motif (110–116 HIHLHVL) and the catalytic triad Cys84-Asp87-His114 in the C-terminal region. Thus, zinc probably provided by the RGSZ2–nNOS complex may bind to Cys84 to block HINT1 isopeptidase activity. Innovation: To date, HINT1 is the only sumoylase that is regulated by two alternate pathways, redox- and calcium-activated CaM. Conclusion: The 15 human HINT1 mutants reported to cause ARAN-NM exhibited altered sumoylase activity, which may contribute to the onset of this human motor disease.

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“…HINT1 mutations are most commonly reported from Europe with some cases reported from China and the United States. [10][11][12] In Europe, R37P, C84R, and H112N mutations of the HINT1 gene are reported to be more prevalent. 10 R37P mutation is commonly identified in central, northeast Europe and Turkey.…”

Section: Discussionmentioning

confidence: 99%

A Novel Mutation of HINT1 Gene in an Adolescent Female with Axonal Neuropathy and Neuromyotonia

Kara

Gül

Güneş

et al. 2020

Journal of Pediatric Neurology

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HINT1 gene mutations cause an axonal neuropathy with some specific findings including presence of neuromyotonia, autosomal recessive inheritance, onset in the first decade, and primary motor involvement. We described an 18-year-old female patient who presented to the clinic with gait instability and muscle stiffness. A homozygous novel c.180_181delAT (p.Ser61Profs*8) variant in the HINT1 gene was found by clinical exome analysis. Parents were heterozygous for the same variant. The patient was diagnosed with autosomal recessive axonal neuropathy with neuromyotonia. The presence of neuromyotonia must be evaluated in patients with hereditary axonal neuropathies as this can help the diagnosis prior to genetic testing.

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Novel mutations in HINT1 gene cause the autosomal recessive axonal neuropathy with neuromyotonia

Cited by 22 publications

References 18 publications

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report

HINT1 founder mutation causing axonal neuropathy with neuromyotonia in South America: A case report

The Axonal Motor Neuropathy-Related HINT1 Protein Is a Zinc- and Calmodulin-Regulated Cysteine SUMO Protease

A Novel Mutation of HINT1 Gene in an Adolescent Female with Axonal Neuropathy and Neuromyotonia

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