A novel de novo <i>RNF216</i> mutation associated with autosomal recessive Huntington‐like disorder

Chen, Keliang; Zhao, Guodong; Wang, He; Huang, Yu‐Yuan; Chen, Shi-Dong; Lin, Bi-Ying; Dong, Qiang; Cui, Mei; Yu, Jin‐Tai

doi:10.1002/acn3.51047

Cited by 12 publications

(15 citation statements)

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“…Characteristic bilateral white matter lesions surrounding the basal ganglia, which have been reported to be related to Huntington's disease,(16) were exclusively found in patients with chorea. (4,6,9) RNF216 is a ubiquitin ligase of the RBR class that attaches ubiquitin chains to substrates. For RNF216, various substrates have been reported, including TOLL-like receptors, tumour necrosis factor-receptor associated factor 3 (TRAF3), the autophagy regulator Beclin and the synaptic regulator activity regulated cytoskeleton associated protein (ARC).…”

Section: Discussionmentioning

confidence: 99%

“…(2) Subsequently, more studies on RNF216related disorders have been published. (3)(4)(5)(6)(7)(8)(9)(10) In addition to GHS, some of those patients presented with Huntington-like disease (HLD), 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism) and congenital hypogonadotropic hypogonadism (CHH), con rming the clinical heterogeneity of RNF216-related disorders. (3,4,(8)(9)(10) The inheritance pattern of RNF216-related disorders includes a monogenic recessive pattern and an oligogenic pattern by acting with other genes.…”

Section: Introductionmentioning

confidence: 95%

“…(3)(4)(5)(6)(7)(8)(9)(10) In addition to GHS, some of those patients presented with Huntington-like disease (HLD), 4H syndrome (hypodontia, hypomyelination, ataxia and hypogonadotropic hypogonadism) and congenital hypogonadotropic hypogonadism (CHH), con rming the clinical heterogeneity of RNF216-related disorders. (3,4,(8)(9)(10) The inheritance pattern of RNF216-related disorders includes a monogenic recessive pattern and an oligogenic pattern by acting with other genes. (2,4,10) Several different types of mutations have been observed, comprising missense, nonsense, splice site, and frameshift mutations and large deletions.…”

Section: Introductionmentioning

confidence: 95%

“…(2,4,10) Several different types of mutations have been observed, comprising missense, nonsense, splice site, and frameshift mutations and large deletions. (2,5,9) Although the number of case reports on RNF216-related disorders has been gradually increasing, a comprehensive review that covers all patients thus far is missing. Moreover, group comparisons and phenotype-genotype correlations have not been studied before.…”

Section: Introductionmentioning

confidence: 99%

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Gordon Holmes syndrome and Huntington-like disease: Two types of RNF216-related disorders

Zhang

2022

Preprint

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Background and purpose: Cases of RNF216-related disorders have been reported sporadically. The systemic clinical classification and phenotype-genotype correlations of these disorders have not been fully studied.Methods: We report the case of a patient with a novel homozygous mutation in RNF216 and review the cases of all patients with RNF216 mutations reported in the literature. These patients were classified by clinical phenotypes into those with Gordon Holmes syndrome (GHS) and those with Huntington-like disease (HLD). Clinical and genetic features were compared between the groups.Results: The cases of twenty-one patients from 14 families with RNF216 mutations were identified and collected. Eleven (52.4%) patients presented with GHS, and eight (38.1%) presented with HLD. GHS patients had a younger age of onset (24.2 vs. 36.9 years, P<0.001) and a higher percentage of male patients (81.8% vs. 25.0%, P=0.024) than HLD patients. Five (62.5%) HLD patients had ataxia, but only one (9.1%) GHS patient developed chorea. Male patients had a higher percentage of poor pubertal development than female patients (69.2% vs. 12.5%, P=0.024). White matter lesions and cerebellar atrophy were the most common imaging findings in both groups. The mutations in nine (64.3%) families were inherited in a monogenic recessive pattern, whereas the mutations in five (35.7%) were inherited in an oligogenic pattern by acting with mutations in OTUD4, SRA1 or other unknown genes. All eight mutations found in GHS patients and 57.1% (4/7) of mutations found in HLD patients resulted in amino acid changes or the truncation of the “RING-between-RING” (RBR) domain, which plays a key role in the ubiquitin E3 ligase activity of RNF216.Conclusion: Patients with RNF216 mutations mainly presented with GHS or HLD in a monogenic autosomal-recessive pattern or an oligogenic pattern. The mutations in GHS patients affected the RBR domain and are thought to abrogate ubiquitin E3 ligase activity. The pathogenic mechanism underlying RNF216-related HLD is still unknown.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Gordon Holmes syndrome and Huntington-like disease: Two types of RNF216-related disorders

Zhang

2022

Preprint

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“…A Huntington‐disease‐like (HDL) disorder has been described in four patients from two unrelated Belgian families. One patient had isolated facial, axial and appendicular chorea 101 while the other three displayed ataxia as well as chorea involving limbs and face 101,102 . All had personality changes, inappropriate behavior, and progressive cognitive changes.…”

Section: Movement Disorders With Hypogonadismmentioning

confidence: 97%

Movement Disorders Associated with Hypogonadism

Gonzàlez‐Latapi

Sousa

Lang

2021

Movement Disord Clin Pract

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A variety of movement disorders can be associated with hypogonadism. Identification of this association may aid in guiding workup and reaching an accurate diagnosis. We conducted a comprehensive and structured search to identify the most common movement disorders associated with hypogonadism. Only Case Reports and Case Series articles were included. Ataxia was the most common movement disorder associated with hypogonadism, including entities such as Gordon‐Holmes syndrome, Boucher‐Neuhäuser, Marinesco‐Sjögren and Perrault syndrome. Tremor was also commonly described, particularly with aneuploidies such as Klinefelter syndrome and Jacob's syndrome. Other rare conditions including mitochondrial disorders and Woodhouse‐Sakati syndrome are associated with dystonia and parkinsonism and either hypo or hypergonadotropic hypogonadism. We also highlight those entities where a combination of movement disorders is present. Hypogonadism may be more commonly associated with movement disorders than previously appreciated. It is important for the clinician to be aware of this association, as well as accompanying symptoms in order to reach a precise diagnosis.

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Ring finger protein 216 loss‐of‐function induces white matter hyperintensities by inhibiting oligodendroglia proliferation

Xu,

Chen,

Yuan

et al. 2024

Cell Biochemistry & Function

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White matter hyperintensities (WMHs) refer to a group of diseases with numerous etiologies while oligodendrocytes remain the centerpiece in the pathogenesis of WMHs. Ring Finger Protein 216 (RNF216) encodes a ubiquitin ligase, and its mutation begets WMHs, ataxia, and cognitive decline in patients. Yet no study has revealed the function of RNF216 in oligodendroglia and WHIs before. In this study, we summarized the phenotypes of RNF216‐mutation cases and explored the normal distribution of RNF216 in distinct brain regions and neuronal cells by bioinformatic analysis. Furthermore, MO3.13, a human oligodendrocyte cell line, was applied to study the function alteration after RNF216 knockdown. As a result, WMHs were the most common symptom in RNF216‐mutated diseases, and RNF216 was indeed relatively enriched in corpus callosum and oligodendroglia in humans. The downregulation of RNF216 in oligodendroglia remarkably hampered cell proliferation by inhibiting the Akt pathway while having no significant effect on cell injury and oligodendrocyte maturation. Combining clinical, bioinformatical, and experimental evidence, our study implied the pivotal role of RNF216 in WMHs which might serve as a potent target in the therapy of WMHs.

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A novel de novo RNF216 mutation associated with autosomal recessive Huntington‐like disorder

Cited by 12 publications

References 10 publications

Gordon Holmes syndrome and Huntington-like disease: Two types of RNF216-related disorders

Gordon Holmes syndrome and Huntington-like disease: Two types of RNF216-related disorders

Movement Disorders Associated with Hypogonadism

Ring finger protein 216 loss‐of‐function induces white matter hyperintensities by inhibiting oligodendroglia proliferation

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