PNPT1

protein-coding

polyribonucleotide nucleotidyltransferase 1

Gene summary

The protein encoded by this gene belongs to the evolutionary conserved polynucleotide phosphorylase family comprised of phosphate dependent 3'-to-5' exoribonucleases implicated in RNA processing and degradation. This enzyme is predominantly localized in the mitochondrial intermembrane space and is involved in import of RNA to mitochondria. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency-13 and autosomal recessive nonsyndromic deafness-70. Related pseudogenes are found on chromosomes 3 and 7. [provided by RefSeq, Dec 2012]

Previous symbols:

DFNB70

MANE transcript

NM_033109.5

Inheritance

AR, AD

ClinVar variants

P:78U:361B:186

Top phenotype

Deafness, autosomal recessive 70, with or without adult-onset neurodegeneration

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr2:55,634,061-55,693,863

External References & Databases

Ensembl (ENSG00000138035)

Transcript & Mutation Effects

hg38 • Region Span ~59.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005365

Submitter: G2P

combined oxidative phosphorylation defect type 13STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013977

Submitter: PanelApp Australia

spinocerebellar ataxia type 25LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012103

Submitter: Ambry Genetics

Leigh syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between PNPT1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of February 26, 2020. The PNPT1 gene encodes the mitochondrial polynucleotide phosphorylase (PNPase), which localizes to the mitochondrial intermembrane space and functions in RNA import into the mitochondria. The PNPT1 gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2012 (PMID: 23084291). Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants identified in three cases in three publications (PMIDs: 23084291, 28645153, 30046113). Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by biochemical function, expression, functional alteration in patient cells, and model systems (PMIDs: 20691904, 27759031, 23084291). In summary, there is moderate evidence to support this gene-disease relationship. 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 U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on February 26, 2020 (SOP Version 7).

combined oxidative phosphorylation defect type 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013977

Submitter: Ambry Genetics

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 70LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013978

Submitter: Labcorp Genetics (formerly Invitae)

combined oxidative phosphorylation defect type 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013977

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 25MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012103

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 70STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013978

Submitter: PanelApp Australia

combined oxidative phosphorylation defect type 13DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013977

Submitter: G2P

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 70, with or without adult-onset neurodegenerationAR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Neurologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 23084290; 23084291; 30244537; 35411967

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PNPT1 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 835

Inborn genetic diseasesTotal: 105

PNPT1-related disorderTotal: 70

not specifiedTotal: 69

Combined oxidative phosphorylation defect type 13Total: 48

Autosomal recessive nonsyndromic hearing loss 70Total: 27

Spinocerebellar ataxia type 25Total: 20

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_033109.5. 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	1 clinvar		3 clinvar	167 clinvar	1 clinvar	172
missense	6 clinvar	15 clinvar	346 clinvar	18 clinvar		385
nonsense	10 clinvar	4 clinvar	1 clinvar			15
start loss						0
frameshift	12 clinvar	10 clinvar	2 clinvar			24
splice donor/acceptor (+/-2bp)	2 clinvar	18 clinvar	9 clinvar			29
Total	31	47	361	185	1	625

Highest pathogenic variant AF is 0.00031839727

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 60 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_033109.5	RefSeq	NP_149100.2	28	MANE Select
ENST00000447944.7	Ensembl	ENSP00000400646.2	28	MANE Select
ENST00000260604.8	Ensembl	ENSP00000260604.4	6	Standard
ENST00000415374.5	Ensembl	ENSP00000393953.1	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Pyrimidine metabolism - Homo sapiens (human)
RNA degradation - Homo sapiens (human)
Purine metabolism - Homo sapiens (human)
Pyrimidine metabolism
Purine metabolism

Biological Process

mitochondrial RNA catabolic process
mitochondrial mRNA catabolic process
positive regulation of mitochondrial RNA catabolic process
mitochondrial RNA processing
mitochondrial RNA 5'-end processing

Molecular Function

3'-5'-exoribonuclease activity
RNA binding
polyribonucleotide nucleotidyltransferase activity
protein binding
poly(U) RNA binding

Cellular Component

nucleus
cytoplasm
mitochondrion
mitochondrial intermembrane space
endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000447944
Coding exons: 28
Length: 59646
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125748
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.424	385	409	0.941	0.0000201	5029
Missense (PolyPhen)		102	131	0.7786		1622
Synonymous	-1.18	164	146	1.12	0.00000785	1518
Loss of Function	4.56	16	51.2	0.313	0.00000256	638

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.000093	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00016	rare
Finnish	0.000095	0.000092	rare
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein implicated in numerous RNA metabolic processes. Catalyzes the phosphorolysis of single-stranded polyribonucleotides processively in the 3'-to-5' direction. Mitochondrial intermembrane factor with RNA-processing exoribonulease activity. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double- stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Required for correct processing and polyadenylation of mitochondrial mRNAs. Plays a role as a cytoplasmic RNA import factor that mediates the translocation of small RNA components, like the 5S RNA, the RNA subunit of ribonuclease P and the mitochondrial RNA-processing (MRP) RNA, into the mitochondrial matrix. Plays a role in mitochondrial morphogenesis and respiration; regulates the expression of the electron transport chain (ETC) components at the mRNA and protein levels. In the cytoplasm, shows a 3'-to-5' exoribonuclease mediating mRNA degradation activity; degrades c-myc mRNA upon treatment with IFNB1/IFN-beta, resulting in a growth arrest in melanoma cells. Regulates the stability of specific mature miRNAs in melanoma cells; specifically and selectively degrades miR-221, preferentially. Plays also a role in RNA cell surveillance by cleaning up oxidized RNAs. Binds to the RNA subunit of ribonuclease P, MRP RNA and miR-221 microRNA. {ECO:0000269|PubMed:12473748, ECO:0000269|PubMed:12721301, ECO:0000269|PubMed:12798676, ECO:0000269|PubMed:16055741, ECO:0000269|PubMed:16410805, ECO:0000269|PubMed:16934922, ECO:0000269|PubMed:18083836, ECO:0000269|PubMed:18083837, ECO:0000269|PubMed:18501193, ECO:0000269|PubMed:19509288, ECO:0000269|PubMed:20547861, ECO:0000269|PubMed:20691904}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 13 (COXPD13) [MIM:614932]: A mitochondrial disorder characterized by early onset severe encephalomyopathy, dystonia, choreoathetosis, bucofacial dyskinesias and combined mitochondrial respiratory chain deficiency. Nerve conductions velocities are decreased. Levels of plasma and cerebrospinal fluid lactate are increased. {ECO:0000269|PubMed:23084291}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal recessive, 70 (DFNB70) [MIM:614934]: A form of non-syndromic deafness characterized by severe, bilateral hearing impairment with prelingual onset, resulting in inability to acquire normal speech. {ECO:0000269|PubMed:23084290}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0952

Intolerance Scores

LoFtool: 0.427
RVIS EVS: 0.14
RVIS percentile EVS: 63.62

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.915

Gene Damage Prediction

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