X-linked diseases: susceptible females

Migeon, Barbara R.

doi:10.1038/s41436-020-0779-4

Cited by 131 publications

(119 citation statements)

References 38 publications

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“…Basically, due to the random lyonization process, female cells usually display random XCI. However, a skewed pattern can be recognized if one of the two X-chromosomes bears gene mutation resulting in the reduced proliferation/survival fitness of particular types of cells [ 63 ]. For example, since functional BTK is required for the differentiation of B cells, female carriers for pathogenic BTK mutation will have only peripheral B cells expressing the wild-type allele, while staminal cells expressing the diseased BTK allele will fail to differentiate into B cells.…”

Section: Discussionmentioning

confidence: 99%

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

et al. 2021

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Primary immunodeficiencies (PIDs) are a large and growing group of disorders commonly associated with recurrent infections. However, nowadays, we know that PIDs often carry with them consequences related to organ or hematologic autoimmunity, autoinflammation, and lymphoproliferation in addition to simple susceptibility to pathogens. Alongside this conceptual development, there has been technical advancement, given by the new but already established diagnostic possibilities offered by new genetic testing (e.g., next-generation sequencing). Nevertheless, there is also the need to understand the large number of gene variants detected with these powerful methods. That means advancing beyond genetic results and resorting to the clinical phenotype and to immunological or alternative molecular tests that allow us to prove the causative role of a genetic variant of uncertain significance and/or better define the underlying pathophysiological mechanism. Furthermore, because of the rapid availability of results, laboratory immunoassays are still critical to diagnosing many PIDs, even in screening settings. Fundamental is the integration between different specialties and the development of multidisciplinary and flexible diagnostic workflows. This paper aims to tell these evolving aspects of immunodeficiencies, which are summarized in five key messages, through introducing and exemplifying five clinical cases, focusing on diseases that could benefit targeted therapy.

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Section: Discussionmentioning

confidence: 99%

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

et al. 2021

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“…Since in most cases the genetic risk variants are present in all cells, this mechanism is relevant only in the context of genetic mosaicism when there are genetically distinct cell populations within the same individual (e.g. Xinactivation) [20][21][22] .…”

Section: Discussionmentioning

confidence: 99%

Genetic mechanisms for tissue-specific essential genes

Dvir

Shohat

Shifman

2021

Preprint

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Genetic diseases often manifest in a specific tissue despite the genetic risk variant being present in all the cells. The most commonly assumed mechanism for this tissue-specificity is the selective expression of the causal gene in the pathogenic tissue, but other possible mechanisms are less explored. Here, using genome-scale CRISPR screens and expression data from approximately 800 cancer cell lines, we identified 1274 tissue-specific essential genes (TSEGs) and show that only a minority of these genes can be explained by preferential expression. To elucidate the mechanisms for the TSEGs we analyzed their association with gene expression. The expression of 115 TSEGs was consistent with preferential expression in the vulnerable tissues. Counterintuitively, for 509 TSEGs we observe a decrease in expression in the vulnerable tissues, which is mainly explained by the increase in gene copy number. Analyzing the expression level of all other genes in the genome identified three other suggested mechanisms for TSEGs. First, based on the expression of paralogs, we observed reduced functional redundancy for 273 TSEGs out of the 741 with known paralogs. Second, in another 118 TSEGs, we found a surprisingly significantly higher expression of their paralogs in the vulnerable tissues, implying functional codependency. Finally, using gene set enrichment analyses, we provide evidence for the remaining 466 TSEGs that the transfer of small molecules to mutant cells by non-mutant cells could explain blood-specific essentiality. Our findings indicate that reliance only on the preferential expression of disease genes may bias views of the disease-relevant tissues.

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“…As a consequence, normal female individuals are naturally mosaic and display organs with a mixed population of cells in which either the paternal or the maternal X has been inactivated. For this reason, women are less susceptible to pathogenic variants on the active X chromosome as the variant will not be expressed in all cells [ 85 ]. This explains why LSDMCA female patients can be observed while nullisomy for these genes in the hemizygous males is lethal as affected fetuses do not survive and are aborted.…”

Section: The Role Of X-chromosome and X-chromosome Inactivationmentioning

confidence: 99%

Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA): An Unconventional Mitochondrial Disorder

Indrieri

Bazzoli

2021

Genes

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Mitochondrial disorders, although heterogeneous, are traditionally described as conditions characterized by encephalomyopathy, hypotonia, and progressive postnatal organ failure. Here, we provide a systematic review of Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA), a rare, unconventional mitochondrial disorder which presents as a developmental disease; its main clinical features include microphthalmia with different degrees of severity, linear skin lesions, and central nervous system malformations. The molecular basis of this disorder has been elusive for several years. Mutations were eventually identified in three X-linked genes, i.e., HCCS, COX7B, and NDUFB11, which are all endowed with defined roles in the mitochondrial respiratory chain. A peculiar feature of this condition is its inheritance pattern: X-linked dominant male-lethal. Only female or XX male individuals can be observed, implying that nullisomy for these genes is incompatible with normal embryonic development in mammals. All three genes undergo X-inactivation that, according to our hypothesis, may contribute to the extreme variable expressivity observed in this condition. We propose that mitochondrial dysfunction should be considered as an underlying cause in developmental disorders. Moreover, LSDMCA should be taken into consideration by clinicians when dealing with patients with microphthalmia with or without associated skin phenotypes.

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X-linked diseases: susceptible females

Cited by 131 publications

References 38 publications

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies

Genetic mechanisms for tissue-specific essential genes

Linear Skin Defects with Multiple Congenital Anomalies (LSDMCA): An Unconventional Mitochondrial Disorder

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