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Oulun yliopiston väitöskirjat

GENETIC CAUSES AND RISK FACTORS ASSOCIATED WITH PHENOTYPES OCCURRING IN MITOCHONDRIAL DISORDERS, ACTA UNIVERSITATIS OULUENSIS D Medica 1419

ISBN-13:	978-952-62-1580-8
Kieli:	englanti
Kustantaja:	Oulun yliopisto
Oppiaine:	Lääketiede
Painos:	Osajulkaisuväitöskirjan yhteenveto-osa
Painosvuosi:	2017
Sijainti:	Print Tietotalo
Sivumäärä:	114
Tekijät:	KYTÖVUORI LAURA

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Finding the genetic causes leading to phenotypes of mitochondrial diseases is challenging because of heterogeneity of the disorders and variety of the underlying biochemical defects. In adults, many of the manifestations of mitochondrial diseases cannot be distinguished from the neurodegenerative processes associated with old age. A single mutation or mutations within the same gene can result in a broad range of disorders. Conversely, clinically similar, monogenic disorders may be caused by genes which are governing entirely different cellular pathways. This study investigated the genetic etiology underlying certain symptoms which are characteristic for mitochondrial syndromes, or mimics of the mitochondrial ones. In the first project, we presented the contribution of genetic variation in the Wolfram Syndrome 1 gene to the risk of diabetes mellitus and sensorineural hearing impairment. We also estimated the frequency of a rare pathogenic variation in WFS1. The second project detected a link between the complex phenotype of age-related hearing impairment and the WFS1 gene. Monogenic forms of ARHI are extremely rare and we succeeded in recognizing one Mendelian form of the trait. The third project confirmed the Mitofusin 2 gene causality in the outlier phenotype of Charcot-Marie-Tooth disease. The fourth project described a Finnish family with two affected siblings with adult-onset ataxia, diabetes mellitus, and hypergonadotropic hypogonadism. The found novel mutation in mtDNA, m.8561C>G, was located in the overlapping region of two mitochondrial genes and resulted in an impaired assembly and dysfunctional energy production of mitochondrial ATP synthase. This thesis expands our knowledge about complex neurological phenotypes and identifies not only some causative genes but also outlier phenotypes, which should be noted in clinical practice.

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