PTHLH
protein-codingparathyroid hormone like hormone, the group of Receptor ligands|Neuropeptides
Gene summary
The protein encoded by this gene is a member of the parathyroid hormone family. This hormone, via its receptor, PTHR1, regulates endochondral bone development and epithelial-mesenchymal interactions during the formation of the mammary glands and teeth. It is responsible for most cases of humoral hypercalcemia of malignancy, and mutations in this gene are associated with brachydactyly type E2 (BDE2). Alternatively spliced transcript variants have been found for this gene. There is also evidence for alternative translation initiation from non-AUG (CUG and GUG) start sites, downstream of the initiator AUG codon, resulting in nuclear forms of this hormone. [provided by RefSeq, Nov 2013]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~14.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0013244
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0013244
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0019677
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0013244
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Dental; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PTHLH variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_198965.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 23 | 24 | |||
| missense | 3 | 65 | 2 | 70 | ||
| nonsense | 8 | 2 | 10 | |||
| start loss | 5 | 5 | ||||
| frameshift | 2 | 3 | 2 | 7 | ||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 3 | |||
| Total | 13 | 11 | 70 | 25 | 0 | 119 |
Highest pathogenic variant AF is 0.000006570993
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_945316.1 | 3 | MANE Select | |
| Ensembl | ENSP00000441765.1 | 3 | MANE Select | |
| RefSeq | NP_002811.1 | 2 | Standard | |
| RefSeq | NP_945315.1 | 2 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| pthlhb | Danio rerio | Structure: ceratohyal bone Quality: deformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endoderm Differentiation
- Vitamin D Receptor Pathway
- Regulation of Apoptosis by Parathyroid Hormone-related Protein
- Endochondral Ossification
- Signaling by GPCR
Biological Process
- skeletal system development
- osteoblast development
- G protein-coupled receptor signaling pathway
- adenylate cyclase-activating G protein-coupled receptor signaling pathway
- cell-cell signaling
Molecular Function
- hormone activity
- peptide hormone receptor binding
Cellular Component
- extracellular region
- extracellular space
- nucleoplasm
- cytoplasm
- Golgi apparatus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000395872
- Coding exons
- 3
- Length
- 14622
- Individuals with no LoFs
- 125736
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 1
- Defined
- 125737
- p
- 0.00000398
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.15 | 74 | 108 | 0.687 | 0.00000660 | 1124 |
| Missense (PolyPhen) | 26 | 46.106 | 0.56392 | 482 | ||
| Synonymous | 1.39 | 33 | 44.9 | 0.735 | 0.00000273 | 361 |
| Loss of Function | 2.62 | 1 | 9.88 | 0.101 | 7.77e-7 | 86 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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. Upregulates BMPR1A expression in the mammary mesenchyme and this increases the sensitivity of these cells to BMPs and allows them to respond to BMP4 in a paracrine and/or autocrine fashion. BMP4 signaling in the mesenchyme, in turn, triggers epithelial outgrowth and augments MSX2 expression, which causes the mammary mesenchyme to inhibit hair follicle formation within the nipple sheath (By similarity). Promotes colon cancer cell migration and invasion in an integrin alpha-6/beta-1- dependent manner through activation of Rac1. {ECO:0000250, ECO:0000269|PubMed:20637541}.;
- Disease
- DISEASE: Brachydactyly E2 (BDE2) [MIM:613382]: A form of brachydactyly. Brachydactyly defines a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. Brachydactyly type E is characterized by shortening of the fingers mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Some individuals are moderately short of stature. In brachydactyly type E2 variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges. {ECO:0000269|PubMed:20170896}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.489
Intolerance Scores
- LoFtool
- 0.239
- RVIS EVS
- 0.06
- RVIS percentile EVS
- 58
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.804
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |