PTS

protein-coding

6-pyruvoyltetrahydropterin synthase

Gene summary

The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

MANE transcript

NM_000317.3

Inheritance

ClinVar variants

P:115U:65B:62

Top phenotype

Hyperphenylalaninemia, BH4-deficient, A

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr11:112,226,367-112,269,955

External References & Databases

Ensembl (ENSG00000150787)

Transcript & Mutation Effects

hg38 • Region Span ~43.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

BH4-deficient hyperphenylalaninemia ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: ClinGen

The relationship between PTS and Biopterin-deficient hyperphenylalaninemia a, an autosomal recessive disorder of biopterin synthesis, was evaluated using the ClinGen Clinical Validity Framework as of December 22nd, 2017. PTS encodes 6-pyruvoyl-tetrahydropterin synthase (PTPS), which catalyzes the second step of biopterin synthesis. Hundreds of patients with deficiency of PTPS activity have been reported (Opladen et al, 2012, PMID 22729819). Variants in PTS were first reported in humans with this disease as early as 1994 (Thöny et al, PMID 8178819). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Fourteen unique variants (missense, frameshift, splice site, inframe deletion, and intronic variants resulting in pseudoexon inclusion) have been reported in humans. Variants in this gene were curated in 9 probands in 5 publications (Thöny et al, 1994; PMID 8178819; Oppliger et al, 1997, PMID 9222757; Meili et al, 2007, PMID 19280650; Leuzzi et al, 2010, PMID 20059486; Brasil et al, 2011, PMID 21542064). More evidence is available in the literature but the maximum score for genetic evidence (12 points ) has been reached. The mechanism for disease is loss of function. This gene-disease relationship is supported by the function of PTPS, which is consistent with the disease process (Takikawa et al, 1986, PMID 3511907; Longo 2009, PMID 19234759), as well as the biochemical features of a null mouse model (Sumi-Ichinose et al, 2001, PMID 11517215). In summary, PTPS is definitively associated with Biopterin-deficient hyperphenylalaninemia a. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. The classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on December 22nd, 2017.

BH4-deficient hyperphenylalaninemia ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: PanelApp Australia

BH4-deficient hyperphenylalaninemia ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: Natera

BH4-deficient hyperphenylalaninemia ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: G2P

BH4-deficient hyperphenylalaninemia ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: Orphanet

BH4-deficient hyperphenylalaninemia ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009863

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperphenylalaninemia, BH4-deficient, AAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

Rationale: Dietary measures and/or medical treatment (eg, L-dopa, tetrahydrobiopterin) can be beneficial

Refs: 7094929; 6142058; 3297709; 3308682; 8178819; 9222757; 9222755; 2027491; 11438997; 11916314; 1388593; 16364672; 20059486

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTS variants in ClinVar

9 Conditions Cataloged

6-Pyruvoyl-tetrahydrobiopterin synthase deficiencyTotal: 304

not providedTotal: 54

not specifiedTotal: 30

PTS-related disorderTotal: 23

Inborn genetic diseasesTotal: 13

Hyperphenylalaninemia, bh4-deficient, a, due to partial pts deficiencyTotal: 4

GTP cyclohydrolase I deficiency with hyperphenylalaninemiaTotal: 3

Noonan syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000317.3. 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 clinvar	2 clinvar	60 clinvar		63
missense	10 clinvar	46 clinvar	60 clinvar	2 clinvar		118
nonsense	6 clinvar	6 clinvar				12
start loss	3 clinvar	3 clinvar				6
frameshift	9 clinvar	9 clinvar				18
splice donor/acceptor (+/-2bp)	6 clinvar	16 clinvar	3 clinvar			25
Total	34	81	65	62	0	242

Highest pathogenic variant AF is 0.000049676913

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000317.3	RefSeq	NP_000308.1	6	MANE Select
ENST00000280362.8	Ensembl	ENSP00000280362.3	6	MANE Select
ENST00000524931.1	Ensembl	ENSP00000434688.1	3	Standard
ENST00000524931.2	Ensembl	ENSP00000434688.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Folate biosynthesis - Homo sapiens (human)
Sepiapterin reductase deficiency
Segawa syndrome
Pterine Biosynthesis
Dopa-responsive dystonia

Biological Process

cellular amino acid metabolic process
tetrahydrobiopterin biosynthetic process
central nervous system development
cofactor metabolic process

Molecular Function

6-pyruvoyltetrahydropterin synthase activity
protein binding
identical protein binding
protein homodimerization activity
metal ion binding

Cellular Component

cytoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000280362
Coding exons: 6
Length: 43591
Individuals with no LoFs: 125724
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125746
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.126	76	79.1	0.960	0.00000379	963
Missense (PolyPhen)		24	23.689	1.0131		293
Synonymous	-0.930	36	29.6	1.22	0.00000161	257
Loss of Function	0.0737	8	8.23	0.972	3.54e-7	102

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	0.000046	0.000046	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00010	0.000098	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6- pyruvoyl tetrahydropterin. {ECO:0000269|PubMed:1282802}.;
Disease: DISEASE: Hyperphenylalaninemia, BH4-deficient, A (HPABH4A) [MIM:261640]: An autosomal recessive disorder characterized by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits. Neurological symptoms are unresponsive to the classic phenylalanine-low diet. {ECO:0000269|PubMed:10220141, ECO:0000269|PubMed:10531334, ECO:0000269|PubMed:10585341, ECO:0000269|PubMed:10874306, ECO:0000269|PubMed:11388593, ECO:0000269|PubMed:7493990, ECO:0000269|PubMed:7698774, ECO:0000269|PubMed:8178819, ECO:0000269|PubMed:8707300, ECO:0000269|PubMed:9159737, ECO:0000269|PubMed:9222757, ECO:0000269|PubMed:9450907}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.617

Intolerance Scores

LoFtool: 0.442
RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium