ClinGen Dosage Sensitivity Curation Page

AP1S2

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
17186471 In 3 families with X-linked mental retardation, Tarpey et al. (2006) identified 2 nonsense and 1 consensus splice-site mutation in the AP1S2 gene. In the first family (family 445), 10 males in 4 generations have a Q36X (106C-T) nonsense mutation in exon 2 of AP1S2. In the second family (family 502), 5 males in 3 generations have a R52X (154C-T) nonsense mutation in exon 2 of AP1S2. In the third family, (family 63), 4 males in 3 generations have a 4-bp deletion preceding the splice-acceptor site of exon 3 (180-5del4). In silico analysis predicted that this deletion reduced the strength of the concensus splice-acceptor site form 94% to 0%. It is likely to cause skipping of exon 3, causing a translational frameshift and inclusion of 3 novel amino acids, with termination at codon 64. RNA was not available to test the in silico prediction. In all families, the mutation segregates completely with disease.
17617514 In a 3 generation family with X-linked mental retardation, Saillour et al. (2007) identified a Q66X (226C-T) nonsense mutation in exon 3 of the AP1S2 gene in 4 affected individuals. The mutation was not identified in more than 160 normal X chromosomes.

Haploinsufficiency phenotype comments:

X-linked recessive mutations in AP1S2 cause Fried type mental retardation.

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.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

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.