Intermediate alleles of HTT gene in patients with Parkinson’s disease

Болезнь Гентингтона (БГ) - нейродегенеративное заболевание, причиной которого является экспансия числа CAG-повторов в первом экзоне гена HTT. Превышение порога в 36 повторов приводит к БГ. Диапазон от 27 до 35 CAG-повторов составляют так называемые промежуточные аллели, которые, согласно последним данным, модифицируют клинические проявления нейродегенеративных заболеваний. В данном исследовании выявлено два случая носительства промежуточных аллелей с 27 CAG- повторами у пациентов с болезнью Паркинсона (БП). Анализ клинической картины выявил «нетипичность» клинического проявления БП. Таким образом, промежуточные аллели гена HTT оказывают модифицирующее влияние на течение БП. Huntington’s disease (HD) is a neurodegenerative disease, caused by a CAG-repeat expansion in exon 1 of the HTT gene. The number of repeats more than 36 leads to HD. The range of 27-35 CAG-repeats is called as intermediate alleles (IAs). There is a growing evidence of importance of IAs for patients with other neurodegenerative diseases. In this study we have detected two cases of carriage of IAs in patients with Parkinson’s disease (PD). The analysis of clinical picture has revealed atypical clinical features of PD in these individuals. Thus, IAs of HTT gene may provide a modifying effect on clinical features of PD.

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The use of high-resolution melting techniques for mutation screening of diseases caused by trinucleotide repeats expansion, with emphasis on the AR gene

Medical Journal of Indonesia ◽

10.13181/mji.v28i2.3008 ◽

2019 ◽

Vol 28 (2) ◽

pp. 116-22

Author(s):

Achmad Zulfa Juniarto ◽

Mahayu Dewi Ariani ◽

Stefani Harumsari ◽

Nurin Aisyiyah Listyasari ◽

Hardian Hardian ◽

...

Keyword(s):

High Resolution ◽

Sanger Sequencing ◽

High Resolution Melting ◽

Repeat Expansion ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Cag Repeat Expansion ◽

Hrm Analysis ◽

Exon 1

BACKGROUND Trinucleotide repeat expansion (TRE) diseases are genetic diseases caused by an increase in the number of CAG, CGG, and CTG codons. CAG repeat expansion in exon 1 of the androgen receptor (AR) gene is known to be associated with disorders of sex development (DSD) and spinal and bulbar muscular atrophy (SBMA). Because the traditional Southern blot for CAG repeat expansion is laborious and time-consuming, this study was aimed to use high-resolution melting (HRM) analysis to screen the CAG repeat length of the AR gene in Indonesian patients with DSD. METHODS In total, 30 male patients with DSD (46, XY), one male patient with SBMA, and 30 healthy males (control) were included in the study. The CAG repeat length was determined using HRM analysis, and Sanger sequencing was used to confirm the CAG repeat length. RESULTS For the DSD cases and controls, the melting temperature (Tm) was within the normal range of 89–91.05°C; however, Tm was 92.65°C for the SBMA case. Sanger sequencing confirmed that DSD cases had 13–27 CAG repeats, and the SBMA case had 54 CAG repeats. CONCLUSIONS HRM analysis using polymerase chain reaction is a sensitive, effective, and rapid technique for screening CAG repeat expansion in exon 1 of the AR gene. This is the first technique for AR gene screening that may be applicable to other TRE diseases.

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No evidence for association of familial Parkinson's disease with CAG repeat expansion

Neurology ◽

10.1212/wnl.45.9.1760 ◽

1995 ◽

Vol 45 (9) ◽

pp. 1760-1763 ◽

Cited By ~ 18

Author(s):

R. Carrero-Valenzuela ◽

K. Lindblad ◽

H. Payami ◽

W. Johnson ◽

M. Schalling ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Repeat Expansion ◽

Cag Repeat ◽

Cag Repeat Expansion ◽

Familial Parkinson’S Disease

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Genetic and Molecular Studies

10.1093/med/9780199929146.003.0006 ◽

2014 ◽

Cited By ~ 1

Author(s):

Cécile Cazeneuve ◽

Alexandra Durr

Keyword(s):

Age Of Onset ◽

Repeat Expansion ◽

Lessons Learned ◽

Cag Repeat ◽

Neurologic Disorder ◽

Cag Repeat Expansion ◽

Large Gene ◽

Different Populations ◽

Intermediate Alleles

Huntington’s disease (HD) is a rare inherited neurologic disorder due to a single mutational mechanism in a large gene (HTT). The mutation is an abnormal CAG repeat expansion, which is translated to a polyglutamine stretch in the huntingtin protein. The growing field of repeat expansion disorders benefits greatly from the lessons learned from the role of the CAG repeat expansion in HD and its resulting phenotype–genotype correlations. The molecular diagnosis can be difficult, and there are some pitfalls for accurate sizing of the CAG repeat, especially in juvenile HD and for intermediate alleles. Correlation between CAG length and age of onset accounts for up to 72% of the variance in different populations, but the search for genes modifying age of onset or progression of HD is still ongoing.

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Spinocerebellar ataxia type 6

Neurology ◽

10.1212/wnl.49.5.1238 ◽

1997 ◽

Vol 49 (5) ◽

pp. 1238-1243 ◽

Cited By ~ 101

Author(s):

R. Matsumura ◽

N. Futamura ◽

Y. Fujimoto ◽

S. Yanagimoto ◽

H. Horikawa ◽

...

Keyword(s):

Family History ◽

Cerebellar Ataxia ◽

Age At Onset ◽

Repeat Expansion ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Cag Repeat Expansion ◽

Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

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α-Synuclein overexpression promotes aggregation of mutant huntingtin

Biochemical Journal ◽

10.1042/bj3460577 ◽

2000 ◽

Vol 346 (3) ◽

pp. 577-581 ◽

Cited By ~ 40

Author(s):

Robert A. FURLONG ◽

Yolanda NARAIN ◽

Julia RANKIN ◽

Andreas WYTTENBACH ◽

David C. RUBINSZTEIN

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Enhanced Green Fluorescent Protein ◽

Fluorescent Protein ◽

Cag Repeats ◽

Mutant Huntingtin ◽

Inclusion Formation ◽

Exon 1 ◽

Green Fluorescent

Protein aggregates are a neuropathological feature of Huntington's disease and Parkinson's disease. Mutant huntingtin exon 1 with 72 CAG repeats fused to enhanced green fluorescent protein (EGFP) forms hyperfluorescent inclusions in PC12 cells. Inclusion formation is enhanced in cells co-transfected with EGFP-huntingtin-(CAG)72 and α-synuclein, a major component of Parkinson's disease aggregates. However, α-synuclein does not form aggregates by itself, nor does it appear in huntingtin inclusions in vitro.

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Clinical Features and Outcomes of Parkinson's Disease with Coronavirus Disease 2019 (COVID-19) in Wuhan: A Single Center, Retrospective, Observational Study

SSRN Electronic Journal ◽

10.2139/ssrn.3605280 ◽

2020 ◽

Author(s):

Heng Zhai ◽

Yinzhang Lv ◽

Yu Xu ◽

Yi Wu ◽

Weiqi Zeng ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Observational Study ◽

Clinical Features ◽

Retrospective Observational Study ◽

Single Center

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Native α-Synuclein, 3-Nitrotyrosine Proteins, and Patterns of Nitro-α-Synuclein-Immunoreactive Inclusions in Saliva and Submandibulary Gland in Parkinson’s Disease

Antioxidants ◽

10.3390/antiox10050715 ◽

2021 ◽

Vol 10 (5) ◽

pp. 715

Author(s):

Emilio Fernández-Espejo ◽

Fernando Rodríguez de Fonseca ◽

Juan Suárez ◽

Eduardo Tolosa ◽

Dolores Vilas ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Nervous System ◽

Clinical Features ◽

Clinical Feature ◽

Similar Concentration ◽

Duct Cells ◽

Nitrative Stress ◽

Salivary Concentration

Background. Salivary α-synuclein (aSyn) and its nitrated form, or 3-nitrotyrosine-α-synuclein (3-NT-αSyn), hold promise as biomarkers for idiopathic Parkinson’s disease (IPD). Nitrative stress that is characterized by an excess of 3-nitrotyrosine proteins (3-NT-proteins) has been proposed as a pathogenic mechanism in IPD. The objective is to study the pathological role of native αSyn, 3-NT-αSyn, and 3-NT-proteins in the saliva and submandibulary glands of patients with IPD. Methods. The salivary and serum αSyn and 3-NT-proteins concentration is evaluated with ELISA in patients and controls. Correlations of αSyn and 3-NT-proteins content with clinical features of the disease are examined. Immunohistochemical 3-NT-αSyn expression in submandibulary gland sections is analyzed. Results. (a) Salivary concentration and saliva/serum ratios of native αSyn and 3-NT-proteins are similar in patients and controls; (b) salivary αSyn and 3-NT-proteins do not correlate with any clinical feature; and (c) three patterns of 3-NT-αSyn-positive inclusions are observed on histological sections: rounded “Lewy-type” aggregates of 10–25 µm in diameter, coarse deposits with varied morphology, and spheroid inclusions or bodies of 3–5 µm in diameter. “Lewy-type” and coarse inclusions are observed in the interlobular connective tissue of the gland, and small-sized bodies are located within the cytoplasm of duct cells. “Lewy-type” inclusions are only observed in patients, and the remaining patterns of inclusions are observed in both the patients and controls. Conclusions. The patients’ saliva presents a similar concentration of native αSyn and 3-nitrotyrosine-proteins than that of the controls, and no correlations with clinical features are found. These findings preclude the utility of native αSyn in the saliva as a biomarker, and they indicate the absence of nitrative stress in the saliva and serum of patients. As regards nitrated αSyn, “Lewy-type” inclusions expressing 3-NT-αSyn are observed in the patients, not the controls—a novel finding that suggests that a biopsy of the submandibulary gland, if proven safe, could be a useful technique for diagnosing IPD. Finally, to our knowledge, this is also the first description of 3-NT-αSyn-immunoreactive intracytoplasmic bodies in cells that are located outside the nervous system. These intracytoplasmic bodies are present in duct cells of submandibulary gland sections from all subjects regardless of their pathology, and they can represent an aging or involutional change. Further immunostaining studies with different antibodies and larger samples are needed to validate the data.

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