QDPR

protein-coding

quinoid dihydropteridine reductase, the group of Short chain dehydrogenase/reductase superfamily

Gene summary

This gene encodes the enzyme dihydropteridine reductase, which catalyzes the NADH-mediated reduction of quinonoid dihydrobiopterin. This enzyme is an essential component of the pterin-dependent aromatic amino acid hydroxylating systems. Mutations in this gene resulting in QDPR deficiency include aberrant splicing, amino acid substitutions, insertions, or premature terminations. Dihydropteridine reductase deficiency presents as atypical phenylketonuria due to insufficient production of biopterin, a cofactor for phenylalanine hydroxylase. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000320.3

Inheritance

ClinVar variants

P:60U:106B:105

Top phenotype

Hyperphenylalaninemia, BH4-deficient, C

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr4:17,460,261-17,512,206

External References & Databases

Ensembl (ENSG00000151552)

Transcript & Mutation Effects

hg38 • Region Span ~51.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

dihydropteridine reductase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009862

Submitter: G2P

dihydropteridine reductase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009862

Submitter: ClinGen

The relationship between QDPR and dihydropteridine reductase (DHPR) deficiency, an autosomal recessive disorder of tetrahydobiopterin regeneration, was evaluated using the ClinGen Clinical Validity Framework as of June 15th, 2018. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in QDPR were first reported in humans with this disease as early as 1998 (Furukawa et al, PMID 9667588). Fifteen unique variants (missense, frameshift, nonsense, intronic, and in frame duplication) were curated in 15 probands from 5 publications (Howells et al, 1990, PMID 2116088; Smooker et al, 1995, PMID 7783174; Ikeda et al, 1997, PMID 9341885; Romstad et al, 2000, PMID 11153907; Ye et al, 2008, PMID 19099731). 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 DHPR, which is consistent with the disease process (PMIDs 14114862, 3033643), as well as the finding of hyperphenylalaninemia in a null mouse model (Xu et al, 2014, PMID 24240194). In summary, QDPR is definitively associated with DHPR deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

dihydropteridine reductase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009862

Submitter: PanelApp Australia

dihydropteridine reductase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009862

Submitter: Orphanet

dihydropteridine reductase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009862

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Hyperphenylalaninemia, BH4-deficient, CAR

Manifestation: Biochemical; Neurologic

Intervention: Biochemical

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

Refs: 53532; 49470; 317358; 2785251; 2116088; 7627180; 10029353; 11153907; 11746132; 16917893

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to QDPR variants in ClinVar

7 Conditions Cataloged

Dihydropteridine reductase deficiencyTotal: 328

not providedTotal: 36

Inborn genetic diseasesTotal: 31

not specifiedTotal: 29

QDPR-related disorderTotal: 8

Inborn errors of metabolismTotal: 1

Hyperphenylalaninemia due to tetrahydrobiopterin deficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000320.3. 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			6 clinvar	103 clinvar		109
missense	8 clinvar	20 clinvar	96 clinvar	2 clinvar		126
nonsense	8 clinvar					8
start loss		1 clinvar				1
frameshift	8 clinvar	5 clinvar				13
splice donor/acceptor (+/-2bp)	5 clinvar	5 clinvar	4 clinvar			14
Total	29	31	106	105	0	271

Highest pathogenic variant AF is 0.000022586773

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 66 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000320.3	RefSeq	NP_000311.2	7	MANE Select
ENST00000281243.10	Ensembl	ENSP00000281243.5	7	MANE Select
NM_001306140.2	RefSeq	NP_001293069.1	6	Standard
ENST00000428702.6	Ensembl	ENSP00000390944.2	6	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

liver development
cellular amino acid metabolic process
L-phenylalanine catabolic process
tetrahydrobiopterin biosynthetic process
response to aluminum ion

Molecular Function

6,7-dihydropteridine reductase activity
electron transfer activity
protein homodimerization activity
NADPH binding
NADH binding

Cellular Component

cytoplasm
cytosol
neuron projection
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281243
Coding exons: 7
Length: 51974
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.285	138	148	0.934	0.00000803	1568
Missense (PolyPhen)		40	57.128	0.70018		600
Synonymous	0.0988	60	61.0	0.984	0.00000396	499
Loss of Function	1.42	8	13.7	0.585	6.89e-7	139

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	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000065	0.000065	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: The product of this enzyme, tetrahydrobiopterin (BH-4), is an essential cofactor for phenylalanine, tyrosine, and tryptophan hydroxylases.;
Disease: DISEASE: Hyperphenylalaninemia, BH4-deficient, C (HPABH4C) [MIM:261630]: Rare autosomal recessive disorder characterized by hyperphenylalaninemia and severe neurologic symptoms (malignant hyperphenylalaninemia) including axial hypotonia and truncal hypertonia, abnormal thermogenesis, and microcephaly. These signs are attributable to depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. Patients do not respond to phenylalanine-restricted diet. HPABH4C is lethal if untreated. {ECO:0000269|PubMed:10408783, ECO:0000269|PubMed:11153907, ECO:0000269|PubMed:2116088, ECO:0000269|PubMed:8326489, ECO:0000269|PubMed:9744478}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.403

Intolerance Scores

LoFtool: 0.243
RVIS EVS: -0.38
RVIS percentile EVS: 27.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.275

Gene Damage Prediction

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