Dosage Compensation in Females with X-Linked Metabolic Disorders

Juchniewicz, Patrycja; Piotrowska, Ewa; Kłoska, Anna; Podlacha, Magdalena; Mantej, Jagoda; Węgrzyn, Grzegorz; Tukaj, Stefan; Jakóbkiewicz‐Banecka, Joanna

doi:10.3390/ijms22094514

Cited by 8 publications

(7 citation statements)

References 201 publications

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“…Moreover, considering the possibility of compensatory changes in MECP2 expression, it is critical to determine the impact of these manipulations on MECP2 expression in unmanipulated, non-target cells in an agespecific manner. Furthermore, we speculate such compensatory mechanisms at the protein level to play crucial roles in other X-linked neurodevelopmental disorders (Brand et al, 2021;Santos-Rebouças et al, 2020) and metabolic disorders (Juchniewicz et al, 2021).…”

Section: Aberrant Homeostasis Of Mecp2 In Late Adolescence As a Catal...mentioning

confidence: 91%

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Mykins

Layo

Dunn

et al. 2022

Preprint

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Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. The underlying mechanisms from normalcy to regression are unclear. Due to random X-chromosome inactivation, female patients of Rett syndrome, and female mouse models of Rett syndrome (Mecp2Heterozygous, Het) express a functional copy of wild-type MECP2 protein in half of all mature cells in brain and body. By analyzing wild-type MECP2 expression in the context of whisker tactile sensory perception, here we report compensatory increase in MECP2 protein expression in 6-week-old adolescent Het mice, which display normal levels of perineuronal net expression, mild tactile sensory perception deficit and efficient pup retrieval behavior. Comparatively, 12-week-old adult Het mice display decreased MECP2 expression and significant tactile sensory perception deficits. Thus, we have identified a period of normalcy and regression in this female mouse model, which coincide with variable wild-type expression of MECP2. We speculate that compensatory increases in MECP2 expression in Het brains allows for normal functioning, while the inability to maintain these expression level changes leads to behavioral deficits.

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Section: Aberrant Homeostasis Of Mecp2 In Late Adolescence As a Catal...mentioning

confidence: 91%

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Mykins

Layo

Dunn

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…In medicine and in clinical practice, sex differences comprise sex-specific and sexrelated diseases, i.e., disease states exclusively or prevalently occurring in people of one sex. Obvious examples of sex-related diseases are genetic diseases linked to sexual chromosomes [1][2][3]. In addition, an impressive list of pathologies includes diseases that display different outcomes in the two sexes, ranging from depression and epilepsy [4,5] to autoimmune diseases [6], and also ranging from myopathies [7] to organ failure or dysfunction [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Sex Differences in Inflammation and Muscle Wasting in Aging and Disease

Peruta

Lozanoska-Ochser

Renzini

et al. 2023

IJMS

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Only in recent years, thanks to a precision medicine-based approach, have treatments tailored to the sex of each patient emerged in clinical trials. In this regard, both striated muscle tissues present significant differences between the two sexes, which may have important consequences for diagnosis and therapy in aging and chronic illness. In fact, preservation of muscle mass in disease conditions correlates with survival; however, sex should be considered when protocols for the maintenance of muscle mass are designed. One obvious difference is that men have more muscle than women. Moreover, the two sexes differ in inflammation parameters, particularly in response to infection and disease. Therefore, unsurprisingly, men and women respond differently to therapies. In this review, we present an up-to-date overview on what is known about sex differences in skeletal muscle physiology and disfunction, such as disuse atrophy, age-related sarcopenia, and cachexia. In addition, we summarize sex differences in inflammation which may underly the aforementioned conditions because pro-inflammatory cytokines deeply affect muscle homeostasis. The comparison of these three conditions and their sex-related bases is interesting because different forms of muscle atrophy share common mechanisms; for instance, those responsible for protein dismantling are similar although differing in terms of kinetics, severity, and regulatory mechanisms. In pre-clinical research, exploring sexual dimorphism in disease conditions could highlight new efficacious treatments or recommend implementation of an existing one. Any protective factors discovered in one sex could be exploited to achieve lower morbidity, reduce the severity of the disease, or avoid mortality in the opposite sex. Thus, the understanding of sex-dependent responses to different forms of muscle atrophy and inflammation is of pivotal importance to design innovative, tailored, and efficient interventions.

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“…S2E). Although all the mutant cell lines can generate cells positive for the three germ layer markers without statistical differences, we observed an inherent variability in the differentiation efficiency among clones that may be due to differences in the genetic backgrounds (heteroplasmy or potential X-linked gene silencing) (Juchniewicz et al, 2021;Lissens et al, 2000;Migeon, 2020).…”

Section: Characterization Of Ipscs Derived From Commercially Availabl...mentioning

confidence: 88%

Human iPSC-derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis

et al. 2022

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Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated human induced pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines. Using whole-exome and mitochondrial sequencing, we identified unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines were viable and capable of differentiating into progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS patient-derived cerebral organoids showed defects in neural epithelial bud generation, size and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural precursor cells with abnormal mitochondrial morphology, characterized by fragmentation and disorganization, and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used to study Leigh syndrome.

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Dosage Compensation in Females with X-Linked Metabolic Disorders

Cited by 8 publications

References 201 publications

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Sex Differences in Inflammation and Muscle Wasting in Aging and Disease

Human iPSC-derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis

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