scholarly journals Assessment of Sacsin Turnover in Patients With ARSACS: Implications for Molecular Diagnosis and Pathogenesis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012962
Author(s):  
Fabiana Longo ◽  
Daniele De Ritis ◽  
Annarita Miluzio ◽  
Davide Fraticelli ◽  
Jonathan Baets ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Phenotypic Variability ◽  
Empirical Studies ◽  
Mechanistic Explanation ◽  
Large Set ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Gene Encoding ◽  
Genotype Phenotype Correlation ◽  
Protein Reduction

Background and Objectives:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge multimodular protein of unknown function. More than 200 SACS mutations have been described worldwide to date. Since ARSACS presents phenotypic variability, previous empirical studies attempted to correlate the nature and position of SACS mutations with the age of onset or with disease severity, though not considering the effect of the various mutations on protein stability. In this work, we studied genotype-phenotype correlation in ARSACS at a functional level.Methods:We analyzed a large set of skin fibroblasts derived from ARSACS patients, including both new and already published cases, carrying mutations of different type affecting diverse domains of the protein.Results:We found that sacsin is almost absent in ARSACS patients, regardless of the nature of the mutation. As expected, we did not detect sacsin in patients with truncating mutations. Interestingly, we found it strikingly reduced or absent also in compound heterozygotes carrying diverse missense mutations. In this case, we excluded SACS mRNA decay, defective translation or faster post-translational degradation as possible causes of protein reduction. Conversely, our results demonstrate that nascent mutant sacsin protein undergoes cotranslational ubiquitination and degradation.Discussion:Our results provide one mechanistic explanation for the lack of genotype-phenotype correlation in ARSACS. We also propose a new and unambiguous criterion for ARSACS diagnosis, that is based on the evaluation of sacsin level. Finally, we identified preemptive degradation of a mutant protein as a novel cause of a human disease.

scholarly journals Sacsin cotranslational degradation causes autosomal recessive spastic ataxia of Charlevoix-Saguenay

2021 ◽  
Author(s):  
Fabiana Longo ◽  
Daniele De Ritis ◽  
Annarita Miluzio ◽  
Davide Fraticelli ◽  
Jonathan Baets ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Age Of Onset ◽  
Diagnostic Algorithm ◽  
Disease Diagnosis ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Gene Encoding ◽  
Spastic Ataxia ◽  
Protein Reduction ◽  
Compound Heterozygotes

AbstractAutosomal recessive spastic ataxia of Charlevoix-Saguenay is caused by more than 200 different mutations in the SACS gene encoding sacsin, a huge multimodular protein of unknown function. ARSACS phenotypic spectrum is highly variable. Previous studies correlated the nature and position of SACS mutations with age of onset or disease severity, though the effects on protein stability were not considered.In this study, we explain mechanistically the lack of genotype-phenotype correlation in ARSACS, with important consequences for disease diagnosis and treatment.We found that sacsin is almost absent in ARSACS fibroblasts, regardless of the nature of the mutation. We did not detect sacsin in patients with truncating mutations, while we found it strikingly reduced or absent also in compound heterozygotes carrying diverse missense mutations. We excluded SACS mRNA decay, defective translation, or faster post-translational degradation as causes of protein reduction. Conversely, we demonstrated that nascent mutant sacsin protein undergoes preemptive cotranslational degradation, emerging as a novel cause of a human disease. Based on these findings, sacsin levels should be included in the diagnostic algorithm for ARSACS.

scholarly journals Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease

2021 ◽  
Author(s):  
Mingming Li ◽  
Jing Ma ◽  
Wenlong Wang ◽  
Xu Yang ◽  
Kaizhong Luo
Keyword(s):  
Wilson Disease ◽  
Large Scale ◽  
Allelic Frequency ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Onset Age ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Nonsense Mutations ◽  
Genotype Phenotype Correlation

Abstract AIM To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype-phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype-phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group.Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 7 mutations had not been previously reported: 1510_1511insA, 2075T>C (Leu692Pro), 2233C>A (Leu745Met), 3209C>G (Pro1070Arg),3677C>T (Thr1226Ile), 3793G>T (Val1265Leu) and 3824T>C (Leu1275Ser). The 2333G>T (Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by 2975C>T (Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The 2333G>T (Arg778 Leu) and 2975C>T (Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hot spot exons. Phenotype-genotype correlation analysis suggested that 2333G>T (Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P=0.034). 2975C>T (Pro992Leu) was correlated with earlier age of disease onset (P=0.002). Additionally, we found that the 3809A>G (Asn1270Ser) mutation significantly indicated younger onset age (P=0.012), and the 3884C>T (Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P=0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P=0.039, P=0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified seven novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

scholarly journals A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiji Guo ◽  
Xia Fang ◽  
Hailei Mao ◽  
Bin Sun ◽  
Jiateng Zhou ◽  
...  
Keyword(s):  
Limb Development ◽  
Missense Variant ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Mutation Site ◽  
Genotype Phenotype Correlation ◽  
Α Helix ◽  
Severe Degree ◽  
Hands And Feet

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

scholarly journals FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation

2003 ◽  
Vol 72 (2) ◽  
pp. 478-487 ◽  
Author(s):  
Elfride De Baere ◽  
Diane Beysen ◽  
Christine Oley ◽  
Birgit Lorenz ◽  
Julie Cocquet ◽  
...  
Keyword(s):  
Phenotypic Variability ◽  
Phenotype Correlation ◽  
Genotype Phenotype Correlation ◽  
Mutational Hotspots

scholarly journals McArdle Disease: Clinical, Biochemical, Histological and Molecular Genetic Analysis of 60 Patients

Biomedicines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 33
Author(s):  
Pushpa Raj Joshi ◽  
Marcus Deschauer ◽  
Stephan Zierz
Keyword(s):  
Genetic Analysis ◽  
Age Of Onset ◽  
Molecular Genetic ◽  
Lactate Production ◽  
Molecular Genetic Analysis ◽  
Exercise Intolerance ◽  
Phenotype Correlation ◽  
Glycogen Accumulation ◽  
Mcardle Disease ◽  
Genotype Phenotype Correlation

A clinical, biochemical, histological and molecular genetic analysis of 60 McArdle patients (33 males and 27 females; mean age at diagnosis: 37 years) was performed. The objective of this study was to identify a possible genotype–phenotype correlation in McArdle disease. All patients complained of exercise-induced myalgia and fatigue; permanent weakness was present in 47% of the patients. Five percent of patients conveyed of masticatory muscle weakness. Age of onset was <15 years in 92% patients. Serum creatine kinase was elevated 5 to13-fold. Forearm ischemic test showed decreased lactate production but excessively increased ammonia upon exercise (n = 16). Muscle biopsies revealed highly reduced or missing myophosphorylase activity (n = 20) (mean: 0.17 ± 0.35 U/g tissue; normal: 12–61) and histologically, sub-sarcolemmal glycogen accumulation (n = 9). Molecular genetic analysis revealed the common p.Arg50Ter mutation in 68% of the patients. Other rather frequent mutations were p.Arg270Ter (allele frequency: 5%) followed by c.2262delA and p.Met1Val (allele frequencies: 3%). Twenty-four other rare mutations were also identified. No genotype–phenotype correlation was observed. The analysis highlights that testing of the p.Arg50Ter mutation could be performed first in molecular genetic testing of patients with exercise intolerance possibly due to McArdle disease. However, there is enormous mutation heterogeneity in McArdle disease thus sequencing of the myophosphorylase gene is needed in patients highly suspicious of McArdle disease.

scholarly journals A Genotype-Phenotype Correlation of Haemophilia a in Victorian Patients with a Description of Novel Mutations

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2498-2498
Author(s):  
Shreerang Sirdesai ◽  
Kerryn Weekes ◽  
Asif Alam ◽  
Huyen A Tran ◽  
Christopher Barnes ◽  
...  
Keyword(s):  
In Silico ◽  
Family Members ◽  
In Silico Analysis ◽  
Clinical Severity ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Novel Mutations ◽  
Mild Phenotype ◽  
Genotype Phenotype Correlation ◽  
Silico Analysis

Abstract Aim: Hemophilia A (HA) is caused by abnormalities in the Factor VIII gene. Certain abnormalities correlate with disease severity. Here, we report the genotype-phenotype correlation for all Victorian HA patients. Methods: Using the Australian Bleeding Disorders Registry, Victorian HA patients were identified. All genetic testing was conducted at Southern Health. The testing algorithm is summarized in Figure 1. Mutations were compared with the list of known Factor 8 mutations on the Champ and EAHAD F8 Variant Databases. A PubMed search was undertaken for any mutations not on either database. If this too was unrevealing, the mutation was designated novel. In-silico analysis was conducted on all novel mutations using three open-access, online prediction tools: a) Mutation Taster; b) Poly-Phen 2; c) Human Splice Site Predictor. Results: 318 patients with matched clinical and genetic records were identified. 275 had known FVIII mutations and 36 novel FVIII mutations were discovered. Eight patients (3%) had no mutations identified. (Table 1) In severe HA the intron-22 inversion was the most common mutation (47/122, 38%). Missense mutations predominated in mild and moderate HA. Inhibitors were present in 44/318 patients, the majority of whom had 26/44 (59%) severe HA. 20/36 novel mutations (55%) were associated with severe HA, 12/36 (33%) with mild HA and 4/36 (11%) with a moderate HA. Novel mutations associated with non-severe phenotypes were mostly missense mutations (15/16); More diversity was seen in the novel mutations causing a severe HA with a fairly even distribution of mutations: missense (7/20), nonsense (4/20) and small deletions and insertions (8/20). One large deletion involving a 6.5kb region of exon 26, as well as one duplication of exons 7 to 9 - was seen in the severe group. In-silico analysis predicted that all novel severe HA mutations were likely to be pathogenic.Inhibitors were seen in 7 patients with novel mutations. Of the 36 novel mutations we described, 9/36 (25%) were seen in other family members - often female carriers. All 9 mutations caused a severe phenotype which is not unexpected given that the screening and testing of family members would be unlikely to take place in patients who have a mild phenotype and rarely require supportive medical care Conclusion: This study adds 36 novel mutations to the currently known FVIII haemophilic mutations. It also confirms that the frequency and correlative clinical severity of known genetic mutations in the Victorian HA cohort is similar to that described internationally. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Spectrum of TGM6-Related Movement Disorders: A New Report with a Pooled Analysis of 48 Patients

2021 ◽  
Author(s):  
Indar Kumar Sharawat ◽  
Prateek Kumar Panda ◽  
Niladri Sekhar Bhunia ◽  
Lesa Dawman
Keyword(s):  
Index Case ◽  
Age Of Onset ◽  
Cerebellar Atrophy ◽  
Pooled Analysis ◽  
Spasmodic Torticollis ◽  
Missense Mutations ◽  
Spinocerebellar Ataxias ◽  
Phenotype Correlation ◽  
Fourth Decade ◽  
Extrapyramidal Features

Abstract Background Spinocerebellar ataxias (SCAs) are a diverse group of progressive neurodegenerative disorders. Until now, more than 20 genes have been implicated to be associated with this phenotype and TGM6 is one of these genes, associated with spinocerebellar ataxia-35 (SCA-35). The majority of disease-causing variants in the TGM6 gene predominantly have been reported from China and Taiwan and the association with Parkinson's disease (PD) have also been reported recently. Methods We report the first Indian case with SCA-35 in a 16-year-old-boy with atypical age of onset at 9 years, prominent extrapyramidal features, intellectual disability, and a novel missense mutation in the TGM6 gene. We also reviewed and collated all previously published cases with pathogenic TGM6 variants. Results Including the index case, 54 cases were identified from 10 relevant articles in literature and 48 cases had adequate clinical details to be included in the pooled analysis. Around two-thirds of reported cases had SCA-35 phenotype, with cerebellar atrophy. Onset in the majority of cases was the fourth decade of life onwards. A proportion of SCA-35 cases also had spasmodic torticollis, impaired proprioception, extrapyramidal features, and myoclonic jerks. The patients with PD had often early-onset milder symptoms, slower progression, and favorable response to levodopa/carbidopa. One patient each presented with episodic ataxia and dystonic tremor of the upper limb. Most of the cases had missense mutations, without any definite hotspot or genotype–phenotype correlation. Conclusions TGM6 mutation should be suspected in patients with SCA like presentation, especially when it is accompanied by extrapyramidal features, spasmodic torticollis, impaired proprioception, or myoclonus.

scholarly journals Factors Affecting Phenotype Variability in a Family with CMT2B: Gender and LRSAM1 Genotype

2016 ◽  
Vol 8 (2) ◽  
pp. 120-126 ◽  
Author(s):  
Leema Reddy Peddareddygari ◽  
Kinsi Oberoi ◽  
Jaasrini Reddy Vellore ◽  
Raji P. Grewal
Keyword(s):  
Age Of Onset ◽  
Novel Mutation ◽  
Phenotypic Variability ◽  
Axonal Neuropathy ◽  
Missense Mutations ◽  
Factors Affecting ◽  
Charcot Marie Tooth Disease ◽  
Marked Variability ◽  
Phenotype Analysis ◽  
Family Gene

Charcot-Marie-Tooth disease type 2 (CMT2) is an autosomal dominant axonal neuropathy caused by mutations in various genes. The subtype CMT2B results from missense mutations in RAB7A, member RAS oncogene family gene, whereas missense mutations in the Leucine-rich repeat and sterile alpha motif-containing protein 1 (LRSAM1) gene cause CMT2P. We describe the genotype/phenotype analysis of a family in which a previously described mutation in the RAB7A gene and a novel mutation in the LRSAM1 gene were identified. In this family, none of the individuals had ulceromutilating features, and there was a marked variability in the age of onset. We discuss the possible etiology of the observed phenotypic variability including the role of gender and possible RAB7A/LRSAM1 gene interactions.

scholarly journals Familial neurohypophyseal diabetes insipidus in 13 kindreds and 2 novel mutations in the vasopressin gene

2019 ◽  
Vol 181 (3) ◽  
pp. 233-244 ◽  
Author(s):  
Giuseppa Patti ◽  
Saverio Scianguetta ◽  
Domenico Roberti ◽  
Alberto Di Mascio ◽  
Antonio Balsamo ◽  
...  
Keyword(s):  
Diabetes Insipidus ◽  
Age Of Onset ◽  
Brain Magnetic Resonance Imaging ◽  
Missense Mutations ◽  
Posterior Pituitary ◽  
Gene Encoding ◽  
Adequate Treatment ◽  
Molecular Features ◽  
Exon 1 ◽  
Magnetic Resonance Imaging Mri

Background Autosomal dominant neurohypophyseal diabetes insipidus (adNDI) is caused by arginine vasopressin (AVP) deficiency resulting from mutations in the AVP-NPII gene encoding the AVP preprohormone. Aim To describe the clinical and molecular features of Italian unrelated families with central diabetes insipidus. Patients and methods We analyzed AVP-NPII gene in 13 families in whom diabetes insipidus appeared to be segregating. Results Twenty-two patients were found to carry a pathogenic AVP-NPII gene mutation. Two novel c.173 G>C (p.Cys58Ser) and c.215 C>A (p.Ala72Glu) missense mutations and additional eight different mutations previously described were identified; nine were missense and one non-sense mutation. Most mutations (eight out of ten) occurred in the region encoding for the NPII moiety; two mutations were detected in exon 1. No mutations were found in exon 3. Median age of onset was 32.5 months with a variability within the same mutation (3 to 360 months). No clear genotype–phenotype correlation has been observed, except for the c.55 G>A (p.Ala19Thr) mutation, which led to a later onset of disease (median age 120 months). Brain magnetic resonance imaging (MRI) revealed the absence of posterior pituitary hyperintensity in 8 out of 15 subjects, hypointense signal in 4 and normal signal in 2. Follow-up MRI showed the disappearance of the posterior pituitary hyperintensity after 6 years in one case. Conclusion adNDI is a progressive disease with a variable age of onset. Molecular diagnosis and counseling should be provided to avoid unnecessary investigations and to ensure an early and adequate treatment.

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