Systematic analysis and prediction of genes associated with disorders on chromosome X

Leitão, Elsa; Schröder, Christopher; Parenti, Ilaria; Dalle, Carine; Rastetter, Agnès; Kühnel, Theresa; Kuechler, Alma; Kaya, Sabine; Gérard, Bénédicte; Schaefer, Eric; Nava, Caroline; Drouot, Nathalie; Engel, Camille; Piard, Juliette; Duban‐Bedu, Bénédicte; Villard, Laurent; Stegmann, Alexander P.A.; Vanhoutte, Els K.; Verdonshot, Job A.J.; Kaiser, Frank J.; Mau-Them, Frédéric Tran; Scala, Marcello; Striano, Pasquale; Frints, Suzanna G.M.; Argilli, Emanuela; Sherr, Elliott H.; Edler, Fikret; Buratti, Julien; Keren, Boris; Mignot, Cyril; Héron, Delphine; Mandel, Jean‐Louis; Gécz, Jozef; Kalscheuer, Vera M.; Horsthemke, Bernhard; Piton, Amélie; Depienne, Christel

doi:10.1101/2022.02.16.22270779

Cited by 8 publications

(7 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the former category, LINKage-speci c-deubiquitylation-de ciency-induced embryonic defects (LINKED) syndrome, has been associated to pathogenic OTUD5 variants only in 2021,(31) whereas PDZD4 and ZMYM3 have been presently only proposed as a disease gene. (33,35) The microdeletion identi ed in ATRX (family 236) highlights the importance of searching for genomic rearrangements, exploiting exome data, or performing genome sequencing. In this case the deletion was missed by CMA due to lack of array probes in the deleted tract.…”

Section: Discussionmentioning

confidence: 99%

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

et al. 2023

View full text Add to dashboard Cite

Despite major technical and genetic advances, more than half of the neurodevelopmental disorders (NDDs) cases remain undiagnosed.We explored the frequency of non-random XCI in the mothers of male patients and in affected females from a clinically heterogeneous cohort of unsolved NDD cases, negative at FRAXA, chromosomal microarray analysis and Trio Exome Sequencing. We hypothesize that an unbalanced XCI could unmask previously discarded genetic variants on the X chromosome connected both to XCI and NDD.A multiplex uorescent-PCR-based assay was used to screen the XCI pattern after methylation sensitive HhaI digestion. Trio-based ES re-analysis was performed in families with skewed XCI occurrence. Linkage analysis and RT-PCR were used to further study the X-chromosome inactive allele. X-drop was used to de ne the chromosome deletion boundaries.We found a skewed XCI (>90%) in 16/186 mothers of affected NDD males (8.6%) and 12/90 female patients (13.3%), far beyond the expected XCI in normal population (3.6%, OR=4.10; OR=2.51). Reanalyzing ES and clinical data, we solved 7/28 cases (25%). These included variants in the KDM5C, PDZD4, PHF6, TAF1, OTUD5, and ZMYM3, and a genomic deletion spanning exons 3-4 of the ATRX gene.The identi cation of a skewed XCI is an easy assay that can help selecting a subgroup of patients for the re-evaluation of X-linked variants, improving the diagnostic yield in NDD patients, and allowing the identi cation of new X-linked disorders.

show abstract

Section: Discussionmentioning

confidence: 99%

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Focusing only on the TM sites might not be enough for visualizing specific effect of drugs on TRPC4/5. Recent genetic study showed that R175C gain of function mutation in TRPC5 cause an impaired intellectual ability (Leitao et al, 2022). In this case, the drug affecting glutathionylation might improve said symptoms.…”

Section: Trpc4/5 Drug Discoverymentioning

confidence: 97%

“…The drugs made so far are concentrated in the membrane area. The GSSG glutathionylation site will be a good target considering the recent results showing the relation of TRPC5 R175C mutation and impaired intellectual ability (Leitao et al, 2022). It is also connected to zinc, which in turn connected to redox sensing and zinc poisoning.…”

Section: Trpc4/5 Drug Discoverymentioning

confidence: 99%

Direct modulation of TRPC ion channels by Gα proteins

Kang,

Kim,

Park

et al. 2024

Front. Physiol.

View full text Add to dashboard Cite

GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action. In gastric smooth muscle, there are two muscarinic acetylcholine receptor (mAChR) subtypes, M2 and M3. M2 receptor activates the muscarinic receptor-operated nonselective cationic current (mIcat, NSCC(ACh)) and induces positive chronotropic effect. Meanwhile, M3 receptor induces hydrolysis of PIP2 and releases DAG and IP3. This IP3 increases intracellular Ca2+ and then leads to contraction of GI smooth muscles. The activation of mIcat is inhibited by anti-Gi/o protein antibodies in GI smooth muscle, indicating the involvement of Gαi/o protein in the activation of mIcat. TRPC4 channel is a molecular candidate for mIcat and can be directly activated by constitutively active GαiQL proteins. TRPC4 and TRPC5 belong to the same subfamily and both are activated by Gi/o proteins. Initial studies suggested that the binding sites for G protein exist at the rib helix or the CIRB domain of TRPC4/5 channels. However, recent cryo-EM structure showed that IYY58-60 amino acids at ARD of TRPC5 binds with Gi3 protein. Considering the expression of TRPC4/5 in the brain, the direct G protein activation on TRPC4/5 is important in terms of neurophysiology. TRPC4/5 channels are also suggested as a coincidence detector for Gi and Gq pathway as Gq pathway increases intracellular Ca2+ and the increased Ca2+ facilitates the activation of TRPC4/5 channels. More complicated situation would occur when GIRK, KCNQ2/3 (IM) and TRPC4/5 channels are co-activated by stimulation of muscarinic receptors at the acetylcholine-releasing nerve terminals. This review highlights the effects of GPCR-Gi protein pathway, including dopamine, μ-opioid, serotonin, glutamate, GABA, on various oragns, and it emphasizes the importance of considering TRPC4/5 channels as crucial players in the field of neuroscience.

show abstract

“…However, some of the X chromosome genes do escape from the described compensation system of inactivation leading to increased gene expression levels in females relative to males (Tukiainen et al, 2017). Since there is accumulating evidence on X chromosome genes being involved in mental function and the control of sex differences during brain development (Skuse, 2005), the escape of inactivation can contribute to sex differences in brain function, cognition and pathology (Leitão et al, 2022). In male mammals, on the other hand, there are genes located on the non-recombining region of the Y chromosome (NRY) that do not exist in females.…”

Section: Sexual Differentiation Of the Braingenetics And Hormonesmentioning

confidence: 99%

Exploring sex differences: insights into gene expression, neuroanatomy, neurochemistry, cognition, and pathology

Lafta,

Mwinyi,

Affatato

et al. 2024

Front. Neurosci.

View full text Add to dashboard Cite

Increased knowledge about sex differences is important for development of individualized treatments against many diseases as well as understanding behavioral and pathological differences. This review summarizes sex chromosome effects on gene expression, epigenetics, and hormones in relation to the brain. We explore neuroanatomy, neurochemistry, cognition, and brain pathology aiming to explain the current state of the art. While some domains exhibit strong differences, others reveal subtle differences whose overall significance warrants clarification. We hope that the current review increases awareness and serves as a basis for the planning of future studies that consider both sexes equally regarding similarities and differences.

show abstract

Systematic analysis and prediction of genes associated with disorders on chromosome X

Cited by 8 publications

References 77 publications

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes

Direct modulation of TRPC ion channels by Gα proteins

Exploring sex differences: insights into gene expression, neuroanatomy, neurochemistry, cognition, and pathology

Contact Info

Product

Resources

About