Heterozygous female carriers of the marker-X-chromosome: IQ estimation and replication status of fra(X)(q)

1984 ◽  
Vol 66 (4) ◽  
pp. 344-346 ◽  
Author(s):  
J. Paul ◽  
Ursula Froster-Iskenius ◽  
W. M�je ◽  
E. Schwinger
Keyword(s):  
X Chromosome ◽  
Heterozygous Female ◽  
Iq Estimation ◽  
Female Carriers

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

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 919 ◽  
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.

scholarly journals Similar Pattern of Increase in FIX Levels in Female Carriers and Males with Hemophilia B Leyden

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Saad Z Ahmed ◽  
Michelle O'Rourke ◽  
Vince Jenkins ◽  
Caitriona Keenan ◽  
Irene Ellen Regan ◽  
...  
Keyword(s):  
Growth Hormone ◽  
X Chromosome ◽  
Hemophilia B ◽  
Proximal Promoter ◽  
Pronounced Increase ◽  
Serial Measurement ◽  
Number Of Patients ◽  
Female Children ◽  
Low Levels ◽  
Female Carriers

Hemophilia B is a congenital X-linked recessive bleeding disorder that occurs as a result of mutations at the long (q) arm of the X chromosome at position 27. Hemophilia B affects 1 in 30,000 males; however the incidence in Ireland is more than double the international incidence and affects 1 in 12,500 male births. Hemophilia B Leyden is a sub-type of hemophilia B first recognized in 1970 in Leyden in the Netherlands. There are more than 20 genetic mutations that result in hemophilia B Leyden. These mutations cluster at three regions within the proximal promoter region of the F9 gene including mutations in nucleotides c.-34 and c.-35 (-5 and -6 legacy numbering) in almost half the cases, mutations around nucleotide c.-49 (-20) and mutations around nucleotide c.-19 (+10). Point mutations associated with hemophilia B Leyden interfere with F9 gene transcription via binding of F9 promoter to ONECUT1 in patients with c.-35 mutation, HNF4a (hepatocyte nuclear factor 4 alpha) in patients with c.-19 mutation and C/EBPa (enhancer-binding protein alpha) in patients with c.-49 mutation. A characteristic feature of hemophilia B Leyden is progressive rise in FIX:C level from the time of puberty to reach lower normal level in young adults. This led to the widely accepted believe that the increase in FIX:C level in hemophilia B Leyden is due to the effect of the androgens surge at puberty. Androgens and anabolic steroids were used for prophylactic treatment in patients with hemophilia B Leyden in a limited number of patients. Recent evidence from animal studies using hypophysectomized hemophilia B Leyden mouse model convincingly demonstrated the pre-eminent role of growth hormone (GH) in regulating the age-dependent increase in FIX:C levels. FIX:C levels were only restored to 10% of pre-hypophysectomy levels by exogenous administration of dihydrotestosterone or oestrodiol but were restored to 80% of pre-hypophysectomy levels by exogenous administration of GH. We investigated the pattern of the increase in FIX:C in 14 male children and four female children from seven different Irish families attending the National Haemophilia Centre at Children's Health Ireland, Crumlin. The hemizygous presence of hemophilia B Leyden associated variant c.35G>A was confirmed by standard dideoxysequence analysis in all children. To evaluate the timing of increase in plasma FIX:C levels, we measured FIX:C levels using automated one stage assay. Serial measurement of FIX:C in male children with hemophilia B leyden demonstrated an increase of FIX:C from severe/moderate levels at the first year of life to mild FIX:C levels within the first 3 years of life. In all 14 male children with hemophilia B Leyden, FIX:C levels increased gradually throughout childhood with more pronounced increase in FIX:C at the time of puberty (Figure 1-A). The increase in FIX:C levels coincided with the known physiological increase in GH levels. Growth hormone level is low during infancy and increases but remains stable at low levels during early childhood, until just before puberty when GH secretion surges to the highest lifetime peak. All four female carriers of hemophilia B Leyden showed low levels of FIX:C at diagnosis associated with variable bleeding symptoms (Figure 1-B). One female child had very low FIX:C level at diagnosis in the moderate hemophilia range (0.04 iu/ml), while all other three female children had low FIX:C levels at the mild hemophilia range at diagnosis (0.13 iu/ml, 0.27 iu/ml and 0.46 iu/ml respectively). Low FIX:C level in those female carriers is likely due to skewed inactivation of the unaffected X chromosome during embryogenesis (lyonization) as no child had compound heterozygosity for the F9 gene mutation and none of the children showed clinical features of Turner syndrome or testicular feminization syndrome. Serial measurement of FIX:C levels in those symptomatic female carriers of hemophilia B Leyden showed similar gradual increase in FIX:C levels during childhood with more steep increase at puberty. Our findings further assert that gender and sex hormones has no influence in the increase of FIX:C level in hemophilia B patients. Figure 1 Disclosures Nolan: Sobi: Other: personal fees; Bayer, CSL Behring, and Sanofi.: Other: sponsorship; Sanofi: Other: PI for sponsor-(Sanofi-) led clinical trial.

Functional analysis of ectodysplasin-A mutations and involvement of X-chromosome inactivation

2021 ◽  
Author(s):  
Yuhua Pan ◽  
Ting Lu ◽  
Ling Peng ◽  
Qi Zeng ◽  
Xiangyu Huang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
X Chromosome ◽  
Pcr Amplification ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Tooth Agenesis ◽  
Human Dental Pulp ◽  
Underlying Mechanisms ◽  
The Impact ◽  
Female Carriers

Abstract Objectives: The aim of this study was to identify genetic clues for the causes of familial non-syndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs).Materials and Methods: Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with EDA mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X chromosome inactivation (XCI) in the blood of female carriers.Results: In this study, we identified an EDA mutation in a Chinese family：the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-κB pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele.Conclusions: In summary, we demonstrated that EDA mutations result in non-syndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-κB signalling pathway in hDPSCs.Clinical Relevance: Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.

An Ashkenazi Jewish founder mutation in CACNA1F causes retinal phenotype in both hemizygous males and heterozygous female carriers

2019 ◽  
Vol 40 (5) ◽  
pp. 443-448 ◽  
Author(s):  
Adva Kimchi ◽  
Vardiella Meiner ◽  
Shira Silverstein ◽  
Michal Macarov ◽  
Hagar Mor-Shaked ◽  
...  
Keyword(s):  
Founder Mutation ◽  
Ashkenazi Jewish ◽  
Heterozygous Female ◽  
Female Carriers

scholarly journals Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

2021 ◽  
Vol 9 ◽  
Author(s):  
Xuening Hou ◽  
Jie Sun ◽  
Chen Liu ◽  
Jihong Hao
Keyword(s):  
X Chromosome ◽  
Clinical Manifestations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Chinese Girl ◽  
Skewed X Chromosome Inactivation ◽  
Female Carriers

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

Expression of the maternally derived X chromosome in the mural trophoblastof the mouse

Development ◽  
1980 ◽  
Vol 56 (1) ◽  
pp. 179-190
Author(s):  
William I. Frels ◽  
Verne M. Chapman
Keyword(s):  
X Chromosome ◽  
Phosphoglycerate Kinase ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Heterozygous Female ◽  
Allelic Form ◽  
Maternal Tissue ◽  
Trophectoderm Cells ◽  
Tissue Contamination ◽  
Selection Of

Only the maternally derived allelic form of the X-chromosome-linked enzyme phosphoglycerate kinase (PGK-1) is observed in the mural trophoblast of heterozygous female progenyin F3 and backcross matings. We have demonstrated that this expression of the maternally derived PGK-1 is not a result of maternal tissue contamination nor of selection of cells expressing the maternal X chromosome (Xm). Our results suggest that the expression of Xm in mural trophoblast is a consequence of nonrandom X-chromosome inactivation in trophectoderm cells.

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