• 0
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PITX3 (HGNC:9006) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
paired like homeodomain 3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
ASMD
Alias symbols
No aliases found
%HI
6.41(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.81(Read more about gnomAD pLI score)
LOEUF
0.48(Read more about gnomAD LOEUF score)
Cytoband
10q24.32
Genomic Coordinates
GRCh37/hg19: chr10:103989946-104001269 NCBI Ensembl UCSC
GRCh38/hg38: chr10:102230189-102241512 NCBI Ensembl UCSC
MANE Select Transcript
NM_005029.4 ENST00000370002.8 (Read more about MANE Select)
Function
Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development. In addition to its importance during development, it also has roles in the long-term survival and maintenance of the mdDA neurons. Activates NR4A2/NURR1-mediated transcription of genes such as SLC6A3, SLC18A2, TH and DRD2 which are essential for development of mdDA neurons. Acts by decreasing the interaction of NR4A2/NURR1 with the corepressor ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-23570
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
No Evidence for Haploinsufficiency (0)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
11/06/2013

Haploinsufficiency (HI) Score Details

HI Score:
0
HI Evidence Strength:
No Evidence for Haploinsufficiency (Disclaimer)
HI Evidence 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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000010.10) (NC_000010.11)