Pathogenicity of mutations in the GDAP1 gene

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Pathogenicity of mutations in the GDAP1 gene

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Title: Pathogenicity of mutations in the GDAP1 gene

Level of degree:

Degree discipline :

medical sciences

Degree grantor:

Instytut Medycyny Doświadczalnej i Klinicznej im. M. Mossakowskiego PAN

Type of object:

Praca dyplomowa

Abstract:

Charcot-Marie-Tooth (CMT) diseases, also known as Hereditary Motor and Sensory Neuropathies (HMSN), are characterized by slowly progressive atrophy and weakness of the muscles, mainly distal upper and lower extremities, and sensory disturbances. One of the causes of CMT diseases is mutations in the GDAP1 (Ganglioside Induced Differentiation Associated Protein 1) gene, which causes several types of polyneuropathy and can be inherited in both autosomal dominant and autosomal recessive ways. However, unlike the autosomal dominant mutations in the GDAP1 gene, which cause the generally mild late-onset CMT-GDAP1 disease, autosomal recessive mutations typically lead to severe hereditary polyneuropathy and motor disabilities as early as the first or second decade of life.The GDAP1 gene encodes a mitochondrial outer membrane protein involved in many key cellular processes, i.e., mitochondrial networking, mitochondrial transport, maintenance of mitochondrial bioenergetics, and calcium homeostasis. The GDAP1 protein is also involved in the regulation of interactions between the mitochondria and the endoplasmic reticulum, and the maintenance of the normal structure of the peroxisomes. However, many aspects of the functioning of the GDAP1 protein, as well as the pathomechanism in which its mutations operate, remain unknown, and the natural course of CMT-GDAP1 disease for individual mutations is quite selectively characterized.The aim of the study was to characterize the "genetic background" accompanying the main pathogenic variants of the GDAP1 gene sequence in patients under the care of the Neuromuscular Disease Unit MMRI PAS to identify molecular and cellular disorders caused by mutations in the GDAP1 gene in the in vitro model of CMT-GDAP1 disease based on human HeLa and SH-SY5Y cells, as well as assessment of pathogenicity of GDAP1 gene sequence variants.In the study group of 14 patients from 9 families affected by CMT-GDAP1 disease, additional rare sequence variants were found in other "CMT genes" following the whole exome sequencing analysis. As "CMT genes" in this work, we accept genes related to pure CMT polyneuropathy and genes related to selected hereditary syndromes in which peripheral polyneuropathy is present. Interestingly, in patients with autosomal dominant GDAP1 mutations, an average of 2 times more sequence variants were identified compared to patients with autosomal recessive mutations. A correlation was observed between the genotype and the clinical phenotype of the studied patients.In the second part of the work, the influence of seven selected mutations of the GDAP1 gene was analyzed. Some of them have been shown to reduce the level of GDAP1 protein and also cause changes in the trans-Golgi part of the TGN. Moreover, it was observed that some of the analyzed GDAP1 gene mutations decreased the viability of the transfected cells.We conclude that the final clinical picture of CMT-GDAP1 disease depends on the type and the presence of sequence variants in other "CMT genes". Furthermore, disturbances in the function and structure of the trans-Golgi appear to play an important role in the molecular pathogenesis of CMT disease caused by mutations in the GDAP1 gene.