LONP1

protein-coding

lon peptidase 1, mitochondrial, the group of Serine proteases|AAA ATPases

Gene summary

This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

Previous symbols:

PRSS15

MANE transcript

NM_004793.4

Inheritance

XL, AR, AD

ClinVar variants

P:34U:389B:501

Top phenotype

Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr19:5,691,834-5,720,572

External References & Databases

Ensembl (ENSG00000196365)

Transcript & Mutation Effects

hg38 • Region Span ~28.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pyruvate dehydrogenase E1-alpha deficiencySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010717

Submitter: Orphanet

CODAS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: Genomics England PanelApp

congenital diaphragmatic herniaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005711

Submitter: G2P

CODAS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: Labcorp Genetics (formerly Invitae)

CODAS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: PanelApp Australia

CODAS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: G2P

CODAS syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: Orphanet

mitochondrial encephalomyopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0004675

Submitter: Ambry Genetics

CODAS syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010879

Submitter: Ambry Genetics

congenital diaphragmatic herniaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005711

Submitter: Ambry Genetics

Leigh syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009723

Submitter: ClinGen

The relationship between LONP1 and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of December 16, 2020. The LONP1 gene encodes a mitochondrial protease with important roles in proteostasis. The LONP1 gene has been reported only once in relation to autosomal recessive Leigh syndrome spectrum, in 2018 (PMID: 29518248). However, defects of this gene are also associated with other mitochondrial phenotypes outside the scope of the Leigh syndrome spectrum gene-disease curation, including CODAS syndrome (cerebral, ocular, dental, auricular, and skeletal anomalies). Evidence supporting the relationship between LONP1 and Leigh syndrome spectrum includes case-level data and experimental data. This curation included two variants identified in one case in one publication (PMID: 29518248). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by expression and animal models (PMIDs: 18853439, 32521756). In summary, there is limited 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 December 16, 2020 (SOP Version 7).

Clinical Genomic Database (CGD)

Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndromeAR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Dental; Musculoskeletal; Neurologic; Ophthalmologic

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

Refs: 25574826

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LONP1 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 1009

Inborn genetic diseasesTotal: 194

LONP1-related disorderTotal: 84

not specifiedTotal: 70

CODAS syndromeTotal: 49

See casesTotal: 3

Neurodevelopmental disorderTotal: 2

ChondrodysplasiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004793.4. 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	296 clinvar	29 clinvar	328
missense	5 clinvar	10 clinvar	368 clinvar	166 clinvar	10 clinvar	559
nonsense	2 clinvar	2 clinvar	5 clinvar			9
start loss						0
frameshift	4 clinvar	8 clinvar	3 clinvar			15
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	10 clinvar			13
Total	12	22	389	462	39	924

Highest pathogenic variant AF is 0.00004021707

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004793.4	RefSeq	NP_004784.2	18	MANE Select
ENST00000360614.8	Ensembl	ENSP00000353826.2	18	MANE Select
NM_001276479.2	RefSeq	NP_001263408.1	19	Standard
NM_001276480.1	RefSeq	NP_001263409.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrial genome maintenance
response to hypoxia
protein quality control for misfolded or incompletely synthesized proteins
mitochondrion organization
aging

Molecular Function

mitochondrial promoter sequence-specific DNA binding
single-stranded DNA binding
single-stranded RNA binding
ATP-dependent peptidase activity
serine-type endopeptidase activity

Cellular Component

nucleus
nucleoplasm
mitochondrion
mitochondrial matrix
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000360614
Coding exons: 18
Length: 28739
Individuals with no LoFs: 125736
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125744
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.428	605	635	0.952	0.0000431	6172
Missense (PolyPhen)		178	242.17	0.73504		2277
Synonymous	-4.80	404	298	1.35	0.0000229	1982
Loss of Function	5.37	5	43.0	0.116	0.00000210	493

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix. May also have a chaperone function in the assembly of inner membrane protein complexes. Participates in the regulation of mitochondrial gene expression and in the maintenance of the integrity of the mitochondrial genome. Binds to mitochondrial promoters and RNA in a single- stranded, site-specific, and strand-specific manner. May regulate mitochondrial DNA replication and/or gene expression using site- specific, single-stranded DNA binding to target the degradation of regulatory proteins binding to adjacent sites in mitochondrial promoters (PubMed:12198491, PubMed:15870080, PubMed:17420247, PubMed:8248235). Endogenous substrates include mitochondrial steroidogenic acute regulatory (StAR) protein, helicase Twinkle (TWNK) and the large ribosomal subunit protein bL32m. bL32m is protected from degradation by LONP1 when it is bound to a nucleic acid (RNA), but TWNK is not (PubMed:17579211, PubMed:28377575). {ECO:0000255|HAMAP-Rule:MF_03120, ECO:0000269|PubMed:12198491, ECO:0000269|PubMed:15870080, ECO:0000269|PubMed:17420247, ECO:0000269|PubMed:17579211, ECO:0000269|PubMed:28377575, ECO:0000269|PubMed:8248235}.;
Disease: DISEASE: CODAS syndrome (CODASS) [MIM:600373]: A rare syndrome characterized by the combination of cerebral, ocular, dental, auricular, and skeletal features. These include developmental delay, craniofacial anomalies, cataracts, ptosis, median nasal groove, delayed tooth eruption, hearing loss, short stature, delayed epiphyseal ossification, metaphyseal hip dysplasia, and vertebral coronal clefts. {ECO:0000269|PubMed:25574826, ECO:0000269|PubMed:25808063}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.425

Intolerance Scores

LoFtool: 0.135
RVIS EVS: -1.82
RVIS percentile EVS: 2.14

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.964

Gene Damage Prediction

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