کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8689814 | 1581068 | 2018 | 45 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Disclosing the functional changes of two genetic alterations in a patient with Chronic Progressive External Ophthalmoplegia: Report of the novel mtDNA m.7486G>A variant
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
علوم اعصاب تکاملی
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چکیده انگلیسی
Chronic Progressive External Ophthalmoplegia (CPEO) is characterized by ptosis and ophthalmoplegia and is usually caused by mitochondrial DNA (mtDNA) deletions or mt-tRNA mutations. The aim of the present work was to clarify the genetic defect in a patient presenting with CPEO and elucidate the underlying pathogenic mechanism. This 62-year-old female first developed ptosis of the right eye at the age of 12 and subsequently the left eye at 45 years, and was found to have external ophthalmoplegia at the age of 55 years. Histopathological abnormalities were detected in the patient's muscle, including ragged-red fibres, a mosaic pattern of COX-deficient muscle fibres and combined deficiency of respiratory chain complexes I and IV. Genetic investigation revealed the “common deletion” in the patient's muscle and fibroblasts. Moreover, a novel, heteroplasmic mt-tRNASer(UCN) variant (m.7486G>A) in the anticodon loop was detected in muscle homogenate (50%), fibroblasts (11%) and blood (4%). Single-fibre analysis showed segregation with COX-deficient fibres for both genetic alterations. Assembly defects of mtDNA-encoded complexes were demonstrated in fibroblasts. Functional analyses showed significant bioenergetic dysfunction, reduction in respiration rate and ATP production and mitochondrial depolarization. Multilamellar bodies were detected by electron microscopy, suggesting disturbance in autophagy. In conclusion, we report a CPEO patient with two possible genetic origins, both segregating with biochemical and histochemical defect. The “common mtDNA deletion” is the most likely cause, yet the potential pathogenic effect of a novel mt-tRNASer(UCN) variant cannot be fully excluded.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neuromuscular Disorders - Volume 28, Issue 4, April 2018, Pages 350-360
Journal: Neuromuscular Disorders - Volume 28, Issue 4, April 2018, Pages 350-360
نویسندگان
Mafalda Bacalhau, Marta Simões, Mariana C. Rocha, Steven A. Hardy, Amy E. Vincent, João Durães, Maria C. Macário, Maria João Santos, Olinda Rebelo, Carla Lopes, João Pratas, Cândida Mendes, Mónica Zuzarte, A. Cristina Rego, Henrique Girão,