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 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.

Missense Mutations of the Tissue-Nonspecific Alkaline Phosphatase Gene in Hypophosphatasia

1992 ◽  
Vol 38 (12) ◽  
pp. 2501-2505 ◽  
Author(s):  
P S Henthorn ◽  
M P Whyte
Keyword(s):  
Alkaline Phosphatase ◽  
Autosomal Recessive ◽  
Bone Mineralization ◽  
Clinical Severity ◽  
Missense Mutations ◽  
Gene Encoding ◽  
Modes Of Transmission ◽  
Pathologic Fractures ◽  
Defective Bone ◽  
Deficient Activity

Abstract Hypophosphatasia is an inborn error of metabolism that is characterized clinically by defective bone mineralization and biochemically by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) in serum and in tissues. Clinical severity is extremely variable, ranging from death in utero to pathologic fractures first presenting in adulthood. Severe forms of the disease are inherited in an autosomal recessive fashion; the modes of transmission of mild forms are uncertain. Deficiency of TNSALP activity in this condition suggests that mutations in the TNSALP "candidate" gene are the primary defects. This hypothesis was supported in 1988 by the demonstration, in one inbred infant, that an identical missense mutation in both alleles of the gene encoding TNSALP caused lethal hypophosphatasia. Here we summarize the work leading to that discovery and discuss the recent identification of additional missense mutations in the TNSALP gene associated with the entire clinical spectrum of hypophosphatasia.

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

2011 ◽  
Vol 26 (12) ◽  
pp. 1585-1589 ◽  
Author(s):  
Vinodh Narayanan ◽  
Stephen G. Rice ◽  
Shannon S. Olfers ◽  
Kumaraswamy Sivakumar
Keyword(s):  
Autosomal Recessive ◽  
Nerve Fibers ◽  
Ophthalmological Examination ◽  
Nonsense Mutations ◽  
Spastic Ataxia ◽  
White American ◽  
Radiological Features ◽  
Sensory Motor ◽  
Allele Specific ◽  
Compound Heterozygotes

Mutations of the SACS gene have been reported in patients with autosomal recessive spastic ataxia of Charlevoix-Saguenay from Canada (Quebec), Tunisia, Japan, Turkey, Belgium, Italy, Spain, the Netherlands, and Germany. Features that distinguish autosomal recessive spastic ataxia of Charlevoix-Saguenay from other recessive ataxias include sensory motor polyneuropathy and hypermyelinated retinal nerve fibers. We describe the clinical, electrophysiological, and radiological features in 2 white American siblings diagnosed with autosomal recessive spastic ataxia of Charlevoix-Saguenay. The 2 affected children are compound heterozygotes for nonsense mutations of the SACS gene (c. 3484 G>T, p. E 1162 X; and c. 11,707 C>T, p. R 3903 X). We have measured allele-specific SACS mRNA abundance in peripheral blood and show that these specific mutant mRNAs are not degraded. We suggest that in children with early onset cerebellar ataxia and spasticity, ophthalmological examination and nerve conduction testing may guide genetic testing.

scholarly journals Usher Syndrome: Genetics of a Human Ciliopathy

2021 ◽  
Vol 22 (13) ◽  
pp. 6723
Author(s):  
Carla Fuster-García ◽  
Belén García-Bohórquez ◽  
Ana Rodríguez-Muñoz ◽  
Elena Aller ◽  
Teresa Jaijo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Retinitis Pigmentosa ◽  
Sensorineural Hearing Loss ◽  
Autosomal Recessive ◽  
Age Of Onset ◽  
Usher Syndrome ◽  
Organ Of Corti ◽  
Sensorineural Hearing ◽  
Protein Network ◽  
Phenotype Correlation

Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation.

scholarly journals The Analysis of Variants in the General Population Reveals That PMM2 Is Extremely Tolerant to Missense Mutations and That Diagnosis of PMM2-CDG Can Benefit from the Identification of Modifiers

2018 ◽  
Vol 19 (8) ◽  
pp. 2218 ◽  
Author(s):  
Valentina Citro ◽  
Chiara Cimmaruta ◽  
Maria Monticelli ◽  
Guglielmo Riccio ◽  
Bruno Hay Mele ◽  
...  
Keyword(s):  
General Population ◽  
Autosomal Recessive ◽  
Biochemical Analysis ◽  
Autosomal Recessive Disease ◽  
Type I ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Phenotypic Spectrum ◽  
Partial Deficiency

Type I disorders of glycosylation (CDG), the most frequent of which is phosphomannomutase 2 (PMM2-CDG), are a group of diseases causing the incomplete N-glycosylation of proteins. PMM2-CDG is an autosomal recessive disease with a large phenotypic spectrum, and is associated with mutations in the PMM2 gene. The biochemical analysis of mutants does not allow a precise genotype–phenotype correlation for PMM2-CDG. PMM2 is very tolerant to missense and loss of function mutations, suggesting that a partial deficiency of activity might be beneficial under certain circumstances. The patient phenotype might be influenced by variants in other genes associated with the type I disorders of glycosylation in the general population.

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 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.

HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence for S65C Implication in Mild Form of Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2502-2505 ◽  
Author(s):  
Catherine Mura ◽  
Odile Raguenes ◽  
Claude Férec
Keyword(s):  
Autosomal Recessive ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Hla Class I ◽  
Missense Mutations ◽  
Mild Form ◽  
C282y Mutation ◽  
Gene Encoding ◽  
Hfe Mutations ◽  
Missense Substitution

Abstract Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A→T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence for S65C Implication in Mild Form of Hemochromatosis

Blood ◽  
1999 ◽  
Vol 93 (8) ◽  
pp. 2502-2505 ◽  
Author(s):  
Catherine Mura ◽  
Odile Raguenes ◽  
Claude Férec
Keyword(s):  
Autosomal Recessive ◽  
Genetic Disorder ◽  
Hereditary Hemochromatosis ◽  
Hla Class I ◽  
Missense Mutations ◽  
Mild Form ◽  
C282y Mutation ◽  
Gene Encoding ◽  
Hfe Mutations ◽  
Missense Substitution

Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A→T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

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