Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

Yao, Xiang; Cheng, Xuewen; Wang, Chong; Zhao, Miao; Guo, Xinxin; Su, Hui-Zhen; Lai, Lu-Lu; Zou, Xiaohuan; Chen, Xue-Jiao; Zhao, Yuying; Dong, En-Lin; Lu, Ying‐Qian; Wu, Shuang; Li, Xiaojuan; Fan, Guang; Yu, Hongjie; Xu, Jianfeng; Wang, Ning; Xiong, Zhi‐Qi; Chen, Wan‐Jin

doi:10.1016/j.neuron.2018.05.037

Cited by 123 publications

(163 citation statements)

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“…Genomic DNA of the probands and all available family members was isolated from peripheral leukocytes using standard protocols. Sanger sequencing was performed on the coding exon (exon 2) of the MYORG gene (NM_020702) with PCR primers as previously described . Cosegregation analysis of the identified mutations was performed on all available family members.…”

Section: Methodssupporting

confidence: 61%

“…To date, biallelic MYORG mutations have been reported in 17 patients (including our cohort). In the previous report, 6 patients with biallelic MYORG mutations exhibited similar symptoms, including slurred speech (6 of 6), ataxia (5 of 6), and cognitive decline (3 of 6), 2 patients presented with migraines, and the other 4 patients seemed asymptomatic . Additional clinical features, including parkinsonism, seizures, psychotic symptoms, dysphagia, urinary disturbance, and constipation, were first observed in our cohort, which further expanded the phenotypic spectrum of PFBC caused by biallelic MYORG mutations.…”

Section: Discussionmentioning

confidence: 92%

“…Cognitive decline (7 of 17; 41.2%) and cerebellar symptoms (6 of 17; 35.3%) were also frequent among patients with biallelic MYORG mutations. Additionally, 4 asymptomatic individuals with biallelic MYORG mutations were noted in the previous report, all of whom carried one or two missense mutations that might partially disrupt protein function. Both intra‐ and interfamilial heterogeneity were present in these patients, as observed in patients with SLC20A2, PDGFRB, PDGFB , or XPR1 mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, a large proportion of patients remain genetically unexplained. Very recently, biallelic mutations in the MYORG gene were identified as a novel genetic cause for autosomal‐recessive PFBC in 12 Chinese patients from six unrelated families …”

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confidence: 99%

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Evaluation of MYORG mutations as a novel cause of primary familial brain calcification

Chen

et al. 2018

Movement Disorders

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Background Very recently, the MYORG gene was identified as a novel causative gene for autosomal‐recessive primary familial brain calcification. Objective To investigate the clinical, genetic, and neuroradiological characteristics of primary familial brain calcification patients with biallelic MYORG mutations in China. Methods We collected clinical and neuroradiological data of 169 Chinese patients with primary familial brain calcification, including 151 sporadic patients and 18 patients from 13 families compatible with an autosomal‐recessive mode of inheritance. Mutational analysis of MYORG was performed in the cohort. Results We identified four, including three novel, MYORG mutations segregating in four families with 5 patients: one nonsense mutation (c.1431C>A, p.Y477*), one missense mutation (c.687G>T, p.W229C), and two nonframeshift indels (c.348_349insCTGGCCTTCCGC, p.116_117insLAFR; c. 428_442delTGCACTTCTTCATCC, p.143_147delLHFFI). The 12‐base‐pair insertion, c.348_349insCTGGCCTTCCGC, was found in either homozygous or heterozygous state in 2 probands of our cohort and another Chinese primary familial brain calcification patient previously reported on in the literature. Haplotype analysis of our patients harboring the insertion indicated a founder effect in the ethnic Han Chinese population. To date, biallelic MYORG mutations have been reported in 17 patients (including our cohort). Most patients were symptomatic (13 of 17; 76.5%), and the most recurrent symptoms were movement disorders (10 of 17; 58.8%), cognitive decline (7 of 17; 41.2%), and cerebellar symptoms (6 of 17; 35.3%). All patients had calcifications on comprehensive cranial CT, most frequently located in the basal ganglia (17 of 17; 100%), cerebellum (17 of 17; 100%), subcortical white matter (14 of 17; 82.4%), and thalamus (13 of 17; 76.5%). Conclusions We confirmed MYORG as a novel causative gene for primary familial brain calcification and further expanded the mutational and phenotypic spectrum of MYORG‐related primary familial brain calcification. © 2018 International Parkinson and Movement Disorder Society

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Section: Methodssupporting

confidence: 61%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Evaluation of MYORG mutations as a novel cause of primary familial brain calcification

Chen

et al. 2018

Movement Disorders

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“…However, there have been few studies reported so far, and the relationship between XPR1 and PFBC still requires further confirmation (Anheim et al., ; Legati et al., ). Very recently, we have identified MYORG as the first autosomal recessive gene for PFBC (Yao et al., ). Subsequently another research group reported a homozygous MYORG mutation in a PFBC patient, further confirming that MYORG is involved in the genetic etiology of PFBC (Peng, Wang, Chen, & Jiang, ).…”

Section: Introductionmentioning

confidence: 99%

Spectrum of SLC20A2 , PDGFRB , PDGFB , and XPR1 mutations in a large cohort of patients with primary familial brain calcification

et al. 2019

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Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC.

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Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation

Lin,

Li,

Chen

et al. 2024

Ann Clin Transl Neurol

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ObjectiveExpand genetic screening for atypical Type I sialidosis (ST‐1) could address its underdiagnosed in both progressive myoclonic ataxia (PMA) and ataxia patients. To evaluate the potential founder effect of mutation in the population.MethodsWe enrolled 231 patients with PMA or ataxia from the First Affiliated Hospital of Fujian Medical University. Through Whole Exome Sequencing and Sanger sequencing, we identified the causative gene in patients. Haplotype analysis was employed to explore a potential founder effect of the NEU1 c.544A>G mutation.ResultsA total of 31 patients from 23 unrelated families were genetically diagnosed with ST‐1. A significant 80.6% of these patients were homozygous for the c.544A>G mutation. We discovered six different NEU1 variants, including two novel mutations: c.951_968del and c.517T>G. The mean age of onset was 18.0 ± 7.1 years. The clinical spectrum of ST‐1 featured ataxia and myoclonus as the most common initial symptoms. Over 40% suffered from controlled generalized tonic–clonic seizures. Mobility and independence varied greatly across the cohort. Cherry‐red spots were rare, occurring in just 9.5% (2/21) of patients. Brain MRIs were typically unremarkable, except for two patients with unusual findings. EEGs showed diffuse paroxysmal activity in 17 patients. The c.544A>G mutation in NEU1 is a founder variant in Fujian, with a unique haplotype prevalent in East Asians.InterpretationST‐1 should be suspected in patients with PMA or ataxia in Southeast China, even without macular cherry‐red spots and seizures, and the premier test could be a variant screening of the founder variant NEU1 c.544A>G.

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Biallelic Mutations in MYORG Cause Autosomal Recessive Primary Familial Brain Calcification

Cited by 123 publications

References 29 publications

Evaluation of MYORG mutations as a novel cause of primary familial brain calcification

Evaluation of MYORG mutations as a novel cause of primary familial brain calcification

Spectrum of SLC20A2 , PDGFRB , PDGFB , and XPR1 mutations in a large cohort of patients with primary familial brain calcification

Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation

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