Tissue-specific distribution of an alternatively spliced COL4A5 isoform and non-random X chromosome inactivation reflect phenotypic variation in heterozygous X-linked Alport syndrome

AbstractFemale somatic X-chromosome inactivation (XCI) balances the X-linked transcriptional dosages between the sexes. Skewed XCI toward one parental X has been observed in several complex human traits, but the extent to which genetics and environment influence skewed XCI is largely unexplored. To address this, we quantify XCI-skew in multiple tissues and immune cell types in a twin cohort. Within an individual, XCI-skew differs between blood, fat and skin tissue, but is shared across immune cell types. XCI skew increases with age in blood, but not other tissues, and is associated with smoking. XCI-skew is increased in twins with Rheumatoid Arthritis compared to unaffected identical co-twins. XCI-skew is heritable in blood of females >55 years old (h2 = 0.34), but not in younger individuals or other tissues. This results in a Gene x Age interaction that shifts the functional dosage of all X-linked heterozygous loci in a tissue-restricted manner.

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Skewed X-chromosome inactivation causes intra-familial phenotypic variation of an EBP mutation in a family with X-linked dominant chondrodysplasia punctata

Human Genetics ◽

10.1007/s00439-002-0844-x ◽

2003 ◽

Vol 112 (1) ◽

pp. 78-83 ◽

Cited By ~ 32

Author(s):

Shuya Shirahama ◽

Akira Miyahara ◽

Hiroshi Kitoh ◽

Akira Honda ◽

Akihiko Kawase ◽

...

Keyword(s):

X Chromosome ◽

Phenotypic Variation ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chondrodysplasia Punctata ◽

Skewed X Chromosome Inactivation

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X-linked CNV and skewed X-chromosome inactivation

Nauchno-prakticheskii zhurnal «Medicinskaia genetika» ◽

10.25557/2073-7998.2020.03.19-21 ◽

2020 ◽

pp. 19-21

Author(s):

Е.А. Фонова ◽

Е.Н. Толмачева ◽

А.А. Кашеварова ◽

М.Е. Лопаткина ◽

К.А. Павлова ◽

...

Keyword(s):

Cell Proliferation ◽

Intellectual Disability ◽

X Chromosome ◽

Copy Number ◽

Copy Number Variations ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Chromosome X ◽

Skewed X Chromosome Inactivation

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).

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Faculty of 1000 evaluation for Cellular resolution maps of x chromosome inactivation: implications for neural development, function, and disease.

F1000 - Post-publication peer review of the biomedical literature ◽

10.3410/f.718235579.793490044 ◽

2014 ◽

Author(s):

Franck Polleux ◽

Julien Courchet

Keyword(s):

X Chromosome ◽

Neural Development ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cellular Resolution

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X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers

Genes ◽

10.3390/genes10110919 ◽

2019 ◽

Vol 10 (11) ◽

pp. 919 ◽

Cited By ~ 1

Author(s):

Viggiano ◽

Madej-Pilarczyk ◽

Carboni ◽

Picillo ◽

Ergoli ◽

...

Keyword(s):

Muscular Dystrophy ◽

X Chromosome ◽

Clinical Symptoms ◽

Fibrous Tissue ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

Cardiac Conduction ◽

Asymptomatic Carriers ◽

Cardiac Symptoms ◽

Female Carriers

X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers—25 familial and 5 sporadic cases—seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

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