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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

Alignment of ALDP proteins in different species.The black bar indicates the position of p.283H in the ALDP sequence.
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pone-0057977-g004: Alignment of ALDP proteins in different species.The black bar indicates the position of p.283H in the ALDP sequence.

Mentions: In the family presented here, a missense mutation (p.His283Arg) was identified, which has not been reported in X-ALD database or other published data, indicating that it is a novel mutation in the ABCD1 gene. For three reasons, it is unlikely a polymorphism or rare variant. First, the mutation was not detected in 200 alleles of normal controls. Second, the histidine at codon 283 is conserved among multiple species (Figure 4). Third, the in silico analysis of pathogenicity was performed using three algorithms (PolyPhen, SIFT and PMut), and all three prediction results revealed that p.His283Arg was classified as pathogenic. The unusual feature of this family is that there are two sisters affected with ALD-AMN, and both of them are heterozygous for this mutation. Having ruled out the possibility that they are compound heterozygotes, we searched for an alternative explanation for their AMN-like phenotype.


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)

Alignment of ALDP proteins in different species.The black bar indicates the position of p.283H in the ALDP sequence.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0057977-g004: Alignment of ALDP proteins in different species.The black bar indicates the position of p.283H in the ALDP sequence.
Mentions: In the family presented here, a missense mutation (p.His283Arg) was identified, which has not been reported in X-ALD database or other published data, indicating that it is a novel mutation in the ABCD1 gene. For three reasons, it is unlikely a polymorphism or rare variant. First, the mutation was not detected in 200 alleles of normal controls. Second, the histidine at codon 283 is conserved among multiple species (Figure 4). Third, the in silico analysis of pathogenicity was performed using three algorithms (PolyPhen, SIFT and PMut), and all three prediction results revealed that p.His283Arg was classified as pathogenic. The unusual feature of this family is that there are two sisters affected with ALD-AMN, and both of them are heterozygous for this mutation. Having ruled out the possibility that they are compound heterozygotes, we searched for an alternative explanation for their AMN-like phenotype.

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