Investigação de mutações nos genes GBA e CHCHD2 em pacientes com doença de Parkinson em uma amostra da população brasileira

• Autor(a) principal: Voigt, Danielle Dutra
• Data de Publicação: 2019
• Tipo de documento: Tese
• Idioma: por
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UNIGRANRIO
• Texto Completo: http://localhost:8080/tede/handle/tede/367
• topic: Biomedicina; Doença de Parkinson; Gene GBA; Gene CHCHD2; Mutações; CIÊNCIAS DA SAÚDE

Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 3% of people over the age of 60 years and is characterized by a multisystemic condition of complex etiology that involves the action of multiple genes, as well as environmental interactions. In addition to monogenic mutations already known that promote changes in proteins, genetic variants of risk also contribute to PD’s susceptibility and may also act as modifiers of disease progression, affecting penetrance, the age of manifestation and its clinical course.The present study, conducted in a Brazilian case, aimed to track mutations throughout the whole extension of the GBA and CHCHD2 genes. The patients were diagnosed by specialists in movement disorders from different hospitals across Brazil (HUPE / RJ, HUCFF / RJ, HUAP / RJ, INDC / RJ, SCMRJ and IINEURO / GO). Molecular analyzes of both genes were performed through automatic sequencing in 304 probands with DP for the GBA gene and 122 with familial PD for the CHCHD2 gene. GBA gene analysis identified 17 exonic alterations (13 missense, 3 synonyms and 1 nonsense) in 37 probands. Among these, three pathogenic alterations were observed [c.1448T>C (L444P), c.1226A>G (N370S) and c.1342G>C (D409H)], all commonly reported in patients with PD of different ethnic groups. In addition, variants c.1049A>G, c.1251G>C and c.1598G>A were observed, not yet described in patients with PD. From the in silico analyzes, six missense alterations [c.1448T> C (L444P), c.1226A> G (N370S) and c.1342G>C (D409H), c.1049A> G) H311R, c.1251G> C (W378C) and c. 703T> C (S196P)], a synonym alteration c.149 7G> C (V460V) and a nonsense alteration c.1598G> A (W533X) were classified as pathogenic. The comparison of this data with those of healthy controls showed significant statistical differences (P = 0.012, OR: 13, 07, 95% CI: 1.72 - 98.98). Analysis of the four exons of the CHCHD2 gene revealed no pathogenic or risk variants in the 122 index case with a family history of PD, corroborating to literature studies carried out in other populations. The present work constitutes the first mention of the presence of CHCHD2 mutations in a Latin American population. Our results suggest that pathogenic variants in this gene not a common cause of familial PD in Brazilian patients.