The Molecular Basis of Severe Hemophilia B in a Girl

Nisen, Perry D.; Stamberg, Judith; Ehrenpreis, Ralph; Llamas‐Velasco, Sara; Shende, Ashok; Engelberg, Jane; Karayalcin, Gungor; Waber, Lewis

doi:10.1056/nejm198610303151806

Cited by 40 publications

(27 citation statements)

References 22 publications

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“…Blood was collected in EDTA tubes. Chromosomal DNA was isolated from white blood cell nuclei as described previously (1). Restriction endonucleases were obtained from New England Biolabs (Beverly, MA), International Biotechnologies, Inc. (New Haven, CT), and Bethesda Research Laboratories (Gaithersburg, MD) and were used according to the conditions specified by the supplier.…”

Section: Methodsmentioning

confidence: 99%

“…In one instance, severe hemophilia B in a girl was due to nonrandom X chromosome inactivation caused by a deletion in one of the X chromosomes distal to a normal Factor IX allele (1). As a means of assessing the extent of nonrandom X chromosome inactivation in other cytogenetically normal females with hemophilia, we used the technique of molecular X chromosome inactivation analysis.…”

Section: Introductionmentioning

confidence: 99%

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Nonrandom X chromosome DNA methylation patterns in hemophiliac females.

Nisen¹,

Waber²

1989

J. Clin. Invest.

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Molecular X chromosome inactivation analysis was used to characterize three females (and their families) with severe hemophilia. First, the maternal and paternal X chromosomes were distinguished by restriction fragment length polymorphisms (RFLPs). Second, the patterns of methylation of X chromosome genes using methylation-sensitive restriction endonucleases were determined. Of the six X chromosome probes tested, only the phosphoglycerol-kinase (PGK) and hypoxanthine-phosphoribosyl-transferase (HPRT) clones were informative, indicating that other X chromosome probes are not useful for X inactivation analysis. After digestion with Hpa II or Hha I, the hybridization intensity of the RFLPs of all three mothers and an unaffected sister were diminished by 50%, consistent with random X chromosome inactivation. The methylation patterns of the X chromosomes of the affected females, however, were clearly nonrandom. Depending upon the probe and the patient, HPRT and PGK sequences were either completely methylated or unmethylated. These findings are extremely suggestive that nonrandom X chromosome inactivation (1yonization) is the basis for severe hemophilia in these females.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nonrandom X chromosome DNA methylation patterns in hemophiliac females.

Nisen¹,

Waber²

1989

J. Clin. Invest.

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“…The identification of females with X-linked recessive disorders has been reported for numerous single gene defects including deficiencies of dystrophin (Duchenne muscular dystrophy), Factor VIII (hemophilia A), and Factor IX (hemophilia B) (1)(2)(3)(4)(5). The expression of these phenotypes in females commonly occurs in association with cytogenetic abnormalities, including 45:XO (Turner's syndrome) and X:autosome translocations.…”

Section: Introductionmentioning

confidence: 99%

“…Such cytogenetic alterations favor the disease state by interrupting sequences important to gene expression or by promoting nonrandom X inactivation. Nonrandom inactivation of structurally abnormal X chromosomes has been well documented and presumably minimizes the deleterious affects of gross chromosomal rearrangements (4,6). We report the identification of a female with hypoxanthine phosphoribosyltransferase (HPRT) deficiency (the Lesch-Nyhan syndrome) whose disease resulted from a de novo deletion ofthe maternal HPRT gene and selection against, or nonrandom inactivation of, the paternal X chromosome.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of a female Lesch-Nyhan patient.

Ogasawara

Stout²,

Goto³

et al. 1989

J. Clin. Invest.

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We report the identification of a female patient with the Xlinked recessive Lesch-Nyhan syndrome (hypoxanthine phosphoribosyltransferase [HPRTI deficiency). Cytogenetic and carrier studies revealed structurally normal chromosomes for this patient and her parents and demonstrated that this mutation arose through a de novo gametic event. Comparison of this patient's DNA with the DNA of her parents revealed that a microdeletion, which occurred within a maternal gamete and involved the entire HPRT gene, was partially responsible for the disease in this patient. Somatic cell hybrids, generated to separate maternal and paternal X chromosomes, showed that expression of two additional X-linked enzymes, phosphoglycerate kinase and glucose-6-phosphate dehydrogenase, were expressed only in cells that contained the maternal X chromosome, suggesting the presence of a functionally inactive paternal X chromosome. Furthermore, comparison of methylation patterns within a region of the HPRT gene known to be important in gene regulation revealed differences between DNA from the father and the patient, in keeping with an active HPRT locus in the father and an inactive HPRT locus in the patient. Together these data indicate that nonrandom inactivation of the cytogenetically normal paternal X chromosome and a microdeletion of the HPRT gene on an active maternal X chromosome were responsible for the absence of HPRT in this patient.

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“…In these cases the normal X chromosomes appear to be preferentially inactivated since the dystrophin levels are below normal, leading to DMD or to a milder variant [14]. On the other hand, a small number of females heterozygous for dystrophin mutations, have most of their normal X chromosome randomly inactivated, and manifest mild DMD symptoms [15]. Furthermore, a different X inactivation pattern was seen in pairs of monozygotic twins heterozygous for mutation in the dystrophin gene, which resulted in clinical manifestation in only one of them [16].…”

Section: Introductionmentioning

confidence: 99%

Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization

Giliberto

Radic

Luce

et al. 2014

Journal of the Neurological Sciences

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Duchenne muscular dystrophy (DMD) is an X-linked recessive disease caused by mutations in the dystrophin gene and is characterized by muscle degeneration and death. DMD affects males; females being asymptomatic carriers of mutations. However, some of them manifest symptoms due to a translocation between X chromosome and an autosome or to a heterozygous mutation leading to inactivation of most of their normal X chromosome. Six symptomatic female carriers and two asymptomatic were analyzed by: I) Segregation of STRs-(CA)n and MLPA assays to detect a hemizygous alteration, and II) X chromosome inactivation pattern to uncover the reason for symptoms in these females. The symptomatic females shared mild but progressive muscular weakness and increased serum creatin kinase (CK) levels. Levels of dystrophin protein were below normal or absent in many fibers. Segregation of STRs-(CA)n revealed hemizygous patterns in three patients, which were confirmed by MLPA. In addition, this analysis showed a duplication in another patient. X chromosome inactivation assay revealed a skewed X inactivation pattern in the symptomatic females and a random inactivation pattern in the asymptomatic ones. Our results support the hypothesis that the DMD phenotype in female carriers of a dystrophin mutation has a direct correlation with a skewed X-chromosome inactivation pattern.

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The Molecular Basis of Severe Hemophilia B in a Girl

Cited by 40 publications

References 22 publications

Nonrandom X chromosome DNA methylation patterns in hemophiliac females.

Nonrandom X chromosome DNA methylation patterns in hemophiliac females.

Molecular analysis of a female Lesch-Nyhan patient.

Symptomatic female carriers of Duchenne muscular dystrophy (DMD): Genetic and clinical characterization

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