Browsing by Subject "MMR"

MLH1 is a gene that codes for one of the four mismatch repair (MMR) proteins alongside MSH2, MSH6, and PMS2. The main function of the MMR proteins is to recognize base mismatches and insertion-deletion loops formed during DNA replication and aid in their excision. Inherited heterozygous pathogenic variants in any of the four MMR genes lead to Lynch syndrome, an inherited cancer syndrome that predisposes to multiple different cancer types, most notably colorectal cancer. Loss of the expression of an MMR gene causes MMR-deficiency, which leads to microsatellite instability, the accumulation of mutations in microsatellite regions of the DNA. The higher mutational burden caused by MMR-deficiency is thought to be the main driving force of genomic instability and tumorigenesis in MMR-deficient cells. In addition to MMR, MLH1 and the MMR machinery have roles in other anticarcinogenic cellular processes, such as DNA damage signaling and DNA double-strand break repair. Recently, MLH1 has also been shown to have a significant role in regulating mitochondrial metabolism and oxidative stress responses. The identification of MMR-proficient tumors in Lynch syndrome patients begs the question whether the lower amount of functional MLH1 observed in MLH1 mutation carriers could cause problems with these functions and pose alternative routes to tumorigenesis. In line with this, it has been shown that the role of MLH1 in cell cycle regulation in DNA damage signaling is notably more sensitive to decreased amount of the protein compared to its role in MMR. The main goal of the thesis was to study the effects of decreased MLH1 expression on gene expression, cellular functions, and possible alternative tumorigenic pathways. In order to achieve this, the coding transcriptome of human fibroblast cell lines expressing MLH1 at different levels was sequenced and the resulting data analyzed. The study revealed that decreased MLH1 expression affects cellular functions associated with mitochondrial function and oxidative stress responses in cells with functional MMR. Particularly NRF2-controlled cytoprotective defence systems were observed to be downregulated. Decreased MLH1 expression was also observed to affect several cellular functions associated with reorganization of the cytoskeleton and interactions with the extracellular matrix. These results strengthen the recently made notions that MLH1 has a role in controlling the function of mitochondria and in mitigating oxidative stress, and that these two functions are connected. The study also brings to light new information on the possible role of MLH1 in controlling the organization of the cytoskeleton, which has previously received little attention. Dysfunction of mitochondria, increased oxidative stress, and reorganization of the cytoskeleton, as a result of decreased MLH1 expression, could pose events that facilitate malignant transformation of cells prior to the total loss of MMR function.

Objectives. Formal musical training has shown promising effects on auditory discrimination in children, but it is not within reach of every family as it is time-consuming and costly. This study aimed to determine whether at-home musical intervention and activities enhance neural auditory speech sound discrimination accuracy in children with or without a familial dyslexia risk. Methods. A follow-up sample of 113 children with or without risk of dyslexia participated. During the first six months of infancy, 57 of the children with a familial risk participated in at-home music listening intervention, including vocal or instrumental music. Musical activities at home were assessed with a questionnaire at 24 months of age. Speech sound discrimination accuracy was assessed at 28 months, with change-elicited responses derived from EEG. Linear mixed-effects (LME) models were applied to study the association between neural responses and musical enrichment. Results. The LME models showed that the association between speech sound discrimination accuracy and musical activities differed between the groups. In post-hoc comparisons, this association differed between the vocal intervention group and the other risk groups. The group without the familial risk did not differ from the risk groups. Conclusions. The observed bidirectional associations of musical activities and vocal listening intervention with change-related cortical processing potentially reflect two separate mechanisms of neural maturation and compensatory activation. Hence, vocal intervention and musical activities might promote specific aspects of auditory neural development. Understanding these associations is relevant in both guiding future research and in preventing language disorders.

Objectives: Dyslexia is a specific reading disorder with a neurobiological and heritable background. Delayed language development and deficient phonological processing have been associated with dyslexia. These linguistic difficulties may relate to atypical speech perception already in early childhood, which could offer a basis for an early identification of dyslexia risk and the development of interventions. In the current study, neural discrimination of speech features was studied in children with a familial risk of dyslexia using the mismatch response (MMR; mismatch negativity, MMN). The aim of the current study was to examine if MMR is atypical in children at risk of dyslexia, and if MMN responses are associated with early language abilities. Methods: 28 children with familial risk of dyslexia and 26 control children participated in EEG recordings and assessment of language abilities at two years of age. MMR amplitudes were recorded for discrimination of vowel duration, pitch, and vowel identity, and groups were compared using MANOVA. Linear regression was applied to examine if MMR responses explained the variation in speech comprehension, production, and vocabulary. Results and Conclusions: Statistically significant MMRs were observed for all features of speech and no group differences were found in MMR amplitudes. This indicates that both groups could discriminate sounds equally well at the automatic level of information processing. MMRs to vowel duration and identity were associated with language comprehension and production, unlike MMR to pitch change. Thus, the perception of phonemic changes seems especially relevant to language development. However, the relationship between MMRs and linguistic abilities differed between the two groups: MMR to vowel duration explained comprehension and production in the control group, whereas MMR to vowel identity explained production in the risk group. A longer follow-up time is needed to examine if MMRs also predict phonological processing and literacy skills in school age.