PubMed ID | Description |
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9489700 | Gleeson et al (1998) described 3 unrelated (sporadic) females with subcortical band heterotopia (see loss phenotype description below) with disruption of the DCX gene. Patient 1 has a 2 basepair AG insertion at position 36, resulting in a frameshift and protein termination at amino acid 24. Patient 2 has a 2 basepair CT deletion at position 684, resulting in a frameshift and protein termination at amino acid 240. Patient 3 has a 2 basepair CT deletion at position 691, resulting in a frameshift and protein termination at amino acid 240. Patient 3 was the only one with parental testing, and the mutation is de novo. In the same paper, Gleeson et al also describe 4 families with different missense mutations in the DCX gene. In each of these families, males carrying the mutation have lissencephaly and females with the mutation have subcortical band heterotopia. |
Males with X-linked lissencephaly (XLIS) caused by mutations in DCX display a phenotype essentially indistinguishable from lissencephaly caused by LIS1 mutations. Affected females heterozygous for DCX mutations show a milder phenotype, presumably representing a mosaic state caused by random inactivation of either the mutant or normal X chromosome. The brains of affected females show a population of neurons that behaves normally and a population that migrates approximately halfway to the cortex and then arrests in the subcortical white matter, producing a band of neurons called subcortical band heterotopia or "doublecortex" (DC). The majority of patients with DC are female, presumably representing mutations in the X-linked locus.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.