ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

  • 10q24.32
  • GRCh37/hg19 chr10: 103,989,946-104,001,231
  • View: NCBI | Ensembl | UCSC
  • GRCh38/hg38 chr10: 102,230,189-102,241,512
  • View: NCBI | Ensembl | UCSC
Select assembly: (NC_000010.10) (NC_000010.11)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Multiple mutations in PITX3 have been reported in association with autosomal dominant and recessive forms of anterior segment mesenchymal dysgenesis and multiple types of cataracts. However, there is not sufficient evidence to conclude that haploinsufficiency is the mechanism for these phenotypes and there is some good evidence that it is not the likely mechanism. Bidinost et al (2006,PMID: 16565358) report a large, consanguineous family with ocular and neurologic phenotypes and a 1-bp deletion. However, the mutation does not perfectly segregate with the ocular phenotype with one carrier who is unaffected and two affected individuals who did not carry the mutation. Sakazume et al. (2007, PMID:17888164) report several families of different ethnic backgrounds with a recurrent 17-bp duplication that leads to a frameshift. Transfection studies with lens epithelial cells showed normal expression and nuclear localization. The protein could bind DNA as monomers but not as complexes and there was reduced luciferase activation. Aldahmesh et al. (2011, PMID: 21836522) report a consanguineous family with homozygous 17-bp deletion (same nucleotides as in the families reported by Sakazume) in severely affected individual and carrier parents who are normal. The resulting protein likely also escapes nonsense-mediated decay and the authors state that this family is evidence against a mechanism of haploinsufficiency. Derwinska et al. (2012, PMID: 22223473) describe a 317 kb deletion involving PITX3 and seven other genes in a 17 year old male with "a Smith-Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior." The authors note that no eye abnormalities were found in the patient, though they did not specify how the patient was evaluated. They point out that PITX3 is involved in the regulation of the development of midbrain dopamine neurons, and report that "analysis of neurotransmitters in [the patient's] cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of [the] patient...led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep." The authors hypothesize that haploinsufficiency of PITX3 resulted in the neurotransmitter phenotype observed in this patient, but no functional studies were performed. They also hypothesize that other heterozygous missense mutations resulting in the ocular phenotypes may be due to gain of function, since their patient (with a deletion involving the entire PITX3 gene) did not display the ocular phenotype.

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