PDSS1

protein-coding

decaprenyl diphosphate synthase subunit 1

Gene summary

The protein encoded by this gene is an enzyme that elongates the prenyl side-chain of coenzyme Q, or ubiquinone, one of the key elements in the respiratory chain. The gene product catalyzes the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. The protein may be peripherally associated with the inner mitochondrial membrane, though no transit peptide has been definitively identified to date. Defects in this gene are a cause of coenzyme Q10 deficiency. [provided by RefSeq, Jul 2008]

Previous symbols:

TPRT

MANE transcript

NM_014317.5

Inheritance

ClinVar variants

P:18U:164B:87

Top phenotype

Coenzyme Q10 deficiency 2

gnomAD constraint

pLI —, LoF o/e 0.61

Max pathogenic AF

—

Genomic locus

chr10:26,697,701-26,746,798

External References & Databases

Ensembl (ENSG00000148459)

Transcript & Mutation Effects

hg38 • Region Span ~49.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

deafness-encephaloneuropathy-obesity-valvulopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013837

Submitter: PanelApp Australia

deafness-encephaloneuropathy-obesity-valvulopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013837

Submitter: Labcorp Genetics (formerly Invitae)

deafness-encephaloneuropathy-obesity-valvulopathy syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013837

Submitter: G2P

deafness-encephaloneuropathy-obesity-valvulopathy syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013837

Submitter: Ambry Genetics

deafness-encephaloneuropathy-obesity-valvulopathy syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013837

Submitter: Orphanet

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *PDSS1* and *PDSS1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 31, 2023. The *PDSS1* gene encodes prenyl diphosphate synthase subunit 1, an enzyme that supplies decaprenyl diphosphate, the precursor for the side chain of the isoprenoid quinone Coenzyme Q10 that functions as a mobile electron carrier in the respiratory chain, as well as other mitochondrial functions including antioxidant properties. A heterodimer is formed by PDSS1 and PDSS2 that functions to isoprenylate benzoquinone in the CoQ10 biosynthesis pathway. The *PDSS1* gene was first reported in relation to *PDSS1*-related primary mitochondrial disease in 2007 (PMID: 17332895). *PDSS1* has been associated with a single disease entity to date, autosomal recessive primary Coenzyme Q10 deficiency 2 [OMIM# 614651]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *PDSS1*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included six unique variants (four missense, two termination) identified in four unrelated cases from four publications (PMIDs: 17332895, 22494076, 34765390, 33285023). Age of onset was early childhood and clinical features in affected individuals include hearing loss, optic atrophy, encephalopathy, livedo reticularis, peripheral neuropathy, nephrotic syndrome, renal failure, pulmonary hypertension, and mild intellectual disability. Brain imaging showed white matter changes and metabolic screening labs showed elevated lactate and decreased Coenzyme Q10. Of note, this expert panel elected to exclude the cases summarized in Jurkute et al., 2022 (PMID: 36266294) given the notable difference in phenotypes reported in this cohort (retinitis pigmentosa and variable hearing loss) and lack of functional evidence providing support for this more mild presentation. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with coenzyme Q10 biosynthetic defects and a *Drosophila melanogaster* model (PMIDs: 17332895, 20889762). In summary, there is moderate evidence to support the relationship between *PDSS1* and *PDSS1*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 31, 2023 (SOP Version 10).

Clinical Genomic Database (CGD)

Coenzyme Q10 deficiency 2AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Endocrine; Gastrointestinal; Hematologic; Musculoskeletal; Neurologic; Renal

Intervention: Biochemical

Rationale: There can be a wide range of manifestations, and in some individuals, treatment with Coenzyme Q10 supplementation can be beneficial

Refs: 17332895; 22231380

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDSS1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 298

Deafness-encephaloneuropathy-obesity-valvulopathy syndromeTotal: 104

Inborn genetic diseasesTotal: 53

not specifiedTotal: 43

PDSS1-related disorderTotal: 8

SchizophreniaTotal: 1

Possible mitochondrial disorder - nuclear genesTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014317.5. 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			3 clinvar	76 clinvar		79
missense	4 clinvar	1 clinvar	148 clinvar	9 clinvar	2 clinvar	164
nonsense		6 clinvar	3 clinvar			9
start loss						0
frameshift	2 clinvar	5 clinvar	7 clinvar			14
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	6	12	164	85	2	269

Highest pathogenic variant AF is 0.00002312916

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014317.5	RefSeq	NP_055132.2	12	MANE Select
ENST00000376215.10	Ensembl	ENSP00000365388.5	12	MANE Select
NM_001321978.2	RefSeq	NP_001308907.1	10	Standard
NM_001321979.2	RefSeq	NP_001308908.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Terpenoid backbone biosynthesis - Homo sapiens (human)
Metabolism
Ubiquinol biosynthesis
Metabolism of cofactors
Metabolism of vitamins and cofactors

Biological Process

ubiquinone biosynthetic process
isoprenoid biosynthetic process
protein heterotetramerization

Molecular Function

trans-hexaprenyltranstransferase activity
metal ion binding
protein heterodimerization activity
trans-octaprenyltranstransferase activity

Cellular Component

mitochondrial matrix
transferase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376215
Coding exons: 12
Length: 49140
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.32	161	215	0.747	0.0000124	2674
Missense (PolyPhen)		50	82.51	0.60598		1024
Synonymous	0.766	69	77.6	0.889	0.00000476	809
Loss of Function	1.85	16	26.2	0.611	0.00000177	285

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Supplies decaprenyl diphosphate, the precursor for the side chain of the isoprenoid quinones ubiquinone-10. {ECO:0000269|PubMed:16262699}.;
Disease: DISEASE: Coenzyme Q10 deficiency, primary, 2 (COQ10D2) [MIM:614651]: An autosomal recessive multisystem disorder characterized by early-onset deafness, optic atrophy, mild mental retardation, peripheral neuropathy, obesity, livedo reticularis, and cardiac valvulopathy. {ECO:0000269|PubMed:17332895}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.290

Intolerance Scores

LoFtool: 0.385
RVIS EVS: 0.06
RVIS percentile EVS: 58.53

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.136

Gene Damage Prediction

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