• 3
    Haplo
    Score
  • 1
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PTHLH (HGNC:9607) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
parathyroid hormone like hormone
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
PTHRP, HHM, PLP, PTHR
%HI
5.78(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
12p11.22
Genomic Coordinates
GRCh37/hg19: chr12:28111017-28125666 NCBI Ensembl UCSC
GRCh38/hg38: chr12:27958084-27972733 NCBI Ensembl UCSC
MANE Select Transcript
NM_198965.2 ENST00000545234.6 (Read more about MANE Select)
Function
Neuroendocrine peptide which is a critical regulator of cellular and organ growth, development, migration, differentiation and survival and of epithelial calcium ion transport. Regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. Required for skeletal homeostasis. Promotes mammary mesenchyme differentiation and bud outgrowth by modulating mesenchymal cell responsiveness to BMPs. Up-regulates BMPR1A expression in the... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-17209
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
Little Evidence for Triplosensitivity (1)
Last Evaluated:
01/25/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
HI Evidence:
  • PUBMED: 20170896
    Klopocki et al. 2010 describe variants in PTHLH in five unrelated families with brachydactyly type E (BDE). The variants include: 1) K120X nonsense variant; 2) pX178WextX*54 non-stop variant (authors propose nonstop-mediated decay as mechanism of LOF); 3) L60P missense variant (authors performed functional test of overexpressing WT and mutant constructs in chicken limb micromass cultures. The authors used alkaline phosphatase activity as the indicator of differentiation. The mutant allele had a weaker suppression of ALP activity; therefore, the authors proposed LOF); 4) L44P missense variant (this variant was not functionally tested); 5) 907 kb deletion including this gene and 5 others which was detected through 7 segregations. The 4 single nucleotide changes were not found in 200 control individuals.
  • PUBMED: 30458061
    Reyes et al. 2018 (PMID: 30458061): The authors describe a female proband with brachydactyly type E (BDE) and no evidence for abnormal calcium or phosphate regulation. Whole exome sequencing (WES) revealed "a novel heterozygous A>G change at nucleotide -3 up-stream of PTHLH exon 3 that encodes the last two amino acids of the pro-sequence and the mature PTHrP...[resulting in] a heterozygous insertion of genomic nucleotides -2 and -1 causing a frame-shift after residue 34 of the preprosequence and thus 29 novel residues without homology to PTHrP or any other protein." This variant was also found in her affected mother, maternal aunt, and monozygous twin sons, but not in her unaffected daughter or sister.
  • PUBMED: 29947179
    Bae et al. 2018 (PMID:29947179): The authors describe a male proband with BDE and normal calcium and phosphate levels. WES of the proband, his affected mother, and his unaffected father revealed a shared c.169C>T (p.Arg57*) variant for the proband and his affected mother. The family history indicates that there are at least 7 other affected relatives across 4 generations of the family, though no other individuals were tested.
  • PUBMED: 26640227
    Thomas-Teinturier et al. 2016 (PMID: 26640227): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH was peformed, and a heterozygous de novo deletion was detected (c.101+3delAAGT). Per the authors, "this alteration deletes four nucleotides from position 3–6 of intron V...[it] is predicted to cause a moderate decrease in the consensus sequence value of the natural donor splice site (WT 84.38; Mut 60.23; Var.% 28.62). As a result, novel additional potential donor sites with a higher consensus value could be created. Use of these sites is predicted to lead to aberrant transcripts with a premature stop codon, as in the first family." Parental relationships were not confirmed. The authors also presented a female proband and her mother with BDE. Single gene sequencing of PTHLH was performed. A heterozygous deletion, c.47_101+73del128 "compris[ing] bases 47–101 of exon V and 73 bases of intron V (total deletion: 128 bp)" was found in the proband and her mother (NM_198965.1). Per the authors: "The c.47_101þ73del128 defect removes the canonical donor site of exon V. Consequently, new potential splice sites localized before or after the deletion breakpoint are predicted to be used. These aberrant splicings are expected to produce transcripts with premature stop codon 5' to the last 50 nucleotides of the penultimate exon [Holbrook et al., 2004], which are predicted to be degraded by nonsense-mediated mRNA decay."
  • PUBMED: 26763883
    Jamsheer et al. 2016 (PMID: 26763883): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH revealed a heterozygous c.166C>T (p.R56*) variant; this variant has been described in an unrelated individual with BDE by Pereda et al. 2017. This variant was said to be de novo, but no information regarding confirmation of parental relationships was presented. The authors also presented a female proband with BDE; her full sister and father were also reported to be affected. Single-gene sequencing revealed a NM_198965.1 c.258delC (p.N87Tfs*18) in exon 4 of PTHLH in the proband and her affected family members, but not in her unaffected mother, sister, or paternal aunt.
  • PUBMED: 28211986
    Pereda et al. 2017 (PMID: 28211986): The authors describe a female proband with BDE and no reported family history. Single gene sequencing of PTHLH revealed a heterozygous c.166C>T (p.R56*) variant; this variant has been described in an unrelated individual with BDE by Jamsheer et al. 2016. The variant was also detected in a mosaic state in the girl's unaffected father (10-20% of blood cells, not detected via buccal swab or hair sample).
HI Evidence Comments:
Additional Evidence: Huang et al. 2019 (PMID: 31283647): The authors describe a 4-generation family affected with BDE and pectus carinatum. Co-segregation of a 3.06 Mb deletion including PTHLH (and 23 other genes) was demonstrated over 9 meioses. 8 unaffected individuals were shown to not carry the deletion. Maass et al 2010 (PMID: 20015959) report a translocation in a patient with Brachydactyly Type E (BDE). The translocation t(8;12)(q13;p11.2) breakpoints are upstream of PTHLH and within KCNB2 on 8q13. The authors used functional studies to show that the derivative chromosome decreased PTHLH activity, thus suggesting downregulation of PTHLH as a cause of BDE. Maass et al (2012, PMID:23093776) report more information on this patient as well as another patient with a t(4;12)(q13.2q13.3;p11.2) and discuss complex findings including the effects of enhancers working in cis and trans on multiple targets. In summary, multiple, presumably loss-of-function variants have been show to segregate, or have arisen de novo in multiple family and individuals with a clinical diagnosis of BDE. Additionally, two multi-gene deletions overlapping PTHLH have been demonstrated to co-segregate across 16 segregations with a clinical phenotype consistent with BDE.

Triplosensitivity (TS) Score Details

TS Score:
1
TS Evidence Strength:
Little Evidence for Triplosensitivity (Disclaimer)
TS Disease:
TS Published Evidence:
  • PUBMED: 26733284
    Flottmann et al. 2016 describe 4 individuals across three generations of a family affected with "short humerus, curved radius, and a specific pattern of hand bone abnormalities, namely extremely short and misshaped metacarpals and middle phalanges with disturbed epiphyseal maturation." ArrayCGH revealed a 70kb duplication in the proband encompassing only the PTHLH gene (arr[hg19] 12p11.22 (28082255–28152554) × 3 (minimal positions)). The duplication segregated with affected status in the family, and was not found in the two unaffected individuals available for testing.
  • PUBMED: 21082660
    Collinson et al. 2010 (PMID: 21082660) report a patient with mesomelic limb shortening and symmetrical enchondromatosis and found a de novo duplication including 12 genes of which PTHLH is involved.
  • PUBMED: 25007883
    Gray et al. 2014 (PMID: 25007883): The authors describe two additional families with acro-osteolysis, bowed long bones, and metaphyseal lesions and multi-gene duplications involving PTHLH and 6 other genes. The duplications are found to have arisen de novo in both families. The first being transmitted from a mosaic father to a heterozygous daughters, whereas the second was also found in a mosaic state having arisen somatically on the maternally derived chromosome.
  • PUBMED: 30803154
    Deshwar et al. 2019 (PMID: 30803154). The authors analyze a patient with a 2.80 Mb deletion located 60kb upstream on PTHLH. The phenotype was consistent with hyperparathyroid disease and included multiple fractures with irregularities. Patient-derived fibroblasts had elevated expression of PTHLH. While speculative, it is possible the reason for this elevated expression is the translocation of a predicted limb enhancer sequence to a position more proximal to the PTHLH promoter.
  • PUBMED: 33981811
    Tacke et al. 2021 (PMID: 33981811). The authors describe a boy with a 898 Kb duplication encompassing PTHLH and 8 other genes. The phenotype was short stature, chest deformity, and multiple fractures. Duplication was not detected in his parents.
TS Evidence Comments:
Copy-number gains affecting PTHLH have been identified in multiple individuals with mesomelic limb shortening, brachydactyly, enchondromatosis, acro-osteolysis, chondrodysplasia, and chest deformity. To date, only a single case has involved PTHLH alone; the others (documented above) also involve other genes. An upstream deletion of leading to upregulation of PTHLH (as measured in patient fibroblasts), was identified in an additional patient with these symptoms. While likely associated with disease reminiscent of hyperparathyroidism, further study is needed to delineate the exact clinical outcome of increased PTHLH dosage.

Genomic View

Select assembly: (NC_000012.11) (NC_000012.12)