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Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree.

Wang Z, Yan A, Lin Y, Xie H, Zhou C, Lan F - PLoS ONE (2013)

Bottom Line: We found a high frequency of skewing in this family.Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.Our data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Fuzhou General Hospital, Fuzhou, China.

ABSTRACT

Background: X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder caused by mutations in the ABCD1 gene. Approximately 20% of X-ALD female carriers may develop neurological symptoms. Skewed X chromosome inactivation (XCI) has been proposed to influence the manifestation of symptoms in X-ALD carriers, but data remain conflicting so far. We identified a three generation kindred, with five heterozygous females, including two manifesting carriers. XCI pattern and the ABCD1 allele expression were assessed in order to determine if symptoms in X-ALD carriers could be related to skewed XCI and whether skewing within this family is more consistent with genetically influenced or completely random XCI.

Results: We found a high frequency of skewing in this family. Four of five females had skewed XCI, including two manifesting carriers favoring the mutant allele, one asymptomatic carrier favoring the normal allele, and one female who was not an X-ALD carrier. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.

Conclusions: Our data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms. Furthermore, XCI skewing in this family is genetically influenced. However, the underlying mechanism remains to be substantiated by further experiments.

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Related in: MedlinePlus

X chromosome inactivation analysis.After digestion with or without Hpa II, DNA was used to amplify a polymorphic CAG repeat within the androgen receptor (AR) gene. The size of the allele is determined by the number of repeats. The area under the peak indicates the degree of amplification of that allele. II5 and II3 inherited the allele 276 from their mother (I 1) and allele 265 from their father, II7 inherited the other allele 286 from I 1. After digestion with Hpa II, their paternal allele was predominantly amplified and represented the inactive. In contrast, III2 inherited the allele 276 from her mother (II3), which was predominantly amplified and represented the inactive. Thus four of them showed skewing of XCI (XCI ratio≥80∶20).
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pone-0057977-g003: X chromosome inactivation analysis.After digestion with or without Hpa II, DNA was used to amplify a polymorphic CAG repeat within the androgen receptor (AR) gene. The size of the allele is determined by the number of repeats. The area under the peak indicates the degree of amplification of that allele. II5 and II3 inherited the allele 276 from their mother (I 1) and allele 265 from their father, II7 inherited the other allele 286 from I 1. After digestion with Hpa II, their paternal allele was predominantly amplified and represented the inactive. In contrast, III2 inherited the allele 276 from her mother (II3), which was predominantly amplified and represented the inactive. Thus four of them showed skewing of XCI (XCI ratio≥80∶20).

Mentions: Digestion with Dde I (Figure 3, left column) showed the manifesting carriers II3 and II5 inherited a 265 bp AR allele from their father and 276 bp allele from their mother (I 1), while their unaffected sister II7 inherited the other 286 bp allele from their mother (I 1), and carrier III2 inherited a 276 bp allele from her mother (II3) and 284 bp allele from her father. Digestion with Hpa II (Figure 3, right column) showed that most of the inactive X chromosomes were of paternal origin in II3 and II5, while the maternal X chromosomes which carried the mutation, were predominantly active. In contrast, the maternal X chromosome of III2 carrying the mutation was predominantly inactive. The ratio of maternal to paternal allele expression was 95∶5, 89∶11, 85∶15 and 10∶90 in II5, II3, II7 and III2, respectively, indicating a high frequency of skewed XCI in the family (Figure 1B). These data also showed that skewed XCI in X-ALD carriers can occur in favor of the mutant or the wild-type allele.


Familial skewed x chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree.

Wang Z, Yan A, Lin Y, Xie H, Zhou C, Lan F - PLoS ONE (2013)

X chromosome inactivation analysis.After digestion with or without Hpa II, DNA was used to amplify a polymorphic CAG repeat within the androgen receptor (AR) gene. The size of the allele is determined by the number of repeats. The area under the peak indicates the degree of amplification of that allele. II5 and II3 inherited the allele 276 from their mother (I 1) and allele 265 from their father, II7 inherited the other allele 286 from I 1. After digestion with Hpa II, their paternal allele was predominantly amplified and represented the inactive. In contrast, III2 inherited the allele 276 from her mother (II3), which was predominantly amplified and represented the inactive. Thus four of them showed skewing of XCI (XCI ratio≥80∶20).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585930&req=5

pone-0057977-g003: X chromosome inactivation analysis.After digestion with or without Hpa II, DNA was used to amplify a polymorphic CAG repeat within the androgen receptor (AR) gene. The size of the allele is determined by the number of repeats. The area under the peak indicates the degree of amplification of that allele. II5 and II3 inherited the allele 276 from their mother (I 1) and allele 265 from their father, II7 inherited the other allele 286 from I 1. After digestion with Hpa II, their paternal allele was predominantly amplified and represented the inactive. In contrast, III2 inherited the allele 276 from her mother (II3), which was predominantly amplified and represented the inactive. Thus four of them showed skewing of XCI (XCI ratio≥80∶20).
Mentions: Digestion with Dde I (Figure 3, left column) showed the manifesting carriers II3 and II5 inherited a 265 bp AR allele from their father and 276 bp allele from their mother (I 1), while their unaffected sister II7 inherited the other 286 bp allele from their mother (I 1), and carrier III2 inherited a 276 bp allele from her mother (II3) and 284 bp allele from her father. Digestion with Hpa II (Figure 3, right column) showed that most of the inactive X chromosomes were of paternal origin in II3 and II5, while the maternal X chromosomes which carried the mutation, were predominantly active. In contrast, the maternal X chromosome of III2 carrying the mutation was predominantly inactive. The ratio of maternal to paternal allele expression was 95∶5, 89∶11, 85∶15 and 10∶90 in II5, II3, II7 and III2, respectively, indicating a high frequency of skewed XCI in the family (Figure 1B). These data also showed that skewed XCI in X-ALD carriers can occur in favor of the mutant or the wild-type allele.

Bottom Line: We found a high frequency of skewing in this family.Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.Our data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms.

View Article: PubMed Central - PubMed

Affiliation: Research Center for Molecular Diagnosis of Genetic Diseases, Fuzhou General Hospital, Fuzhou, China.

ABSTRACT

Background: X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder caused by mutations in the ABCD1 gene. Approximately 20% of X-ALD female carriers may develop neurological symptoms. Skewed X chromosome inactivation (XCI) has been proposed to influence the manifestation of symptoms in X-ALD carriers, but data remain conflicting so far. We identified a three generation kindred, with five heterozygous females, including two manifesting carriers. XCI pattern and the ABCD1 allele expression were assessed in order to determine if symptoms in X-ALD carriers could be related to skewed XCI and whether skewing within this family is more consistent with genetically influenced or completely random XCI.

Results: We found a high frequency of skewing in this family. Four of five females had skewed XCI, including two manifesting carriers favoring the mutant allele, one asymptomatic carrier favoring the normal allele, and one female who was not an X-ALD carrier. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, XIST promoter mutations, were not consistent with our results.

Conclusions: Our data support that skewed XCI in favor of the mutant ABCD1 allele would be associated with the manifestation of heterozygous symptoms. Furthermore, XCI skewing in this family is genetically influenced. However, the underlying mechanism remains to be substantiated by further experiments.

Show MeSH
Related in: MedlinePlus