Human Disease Model Report: mitochondrial complex IV deficiency, nuclear type 5

General Information

Name

mitochondrial complex IV deficiency, nuclear type 5

FlyBase ID

FBhh0000353

Disease Ontology Term

French Canadian Leigh disease

Parent Disease

Leigh syndrome

mitochondrial complex IV deficiency, nuclear type

OMIM

MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5

Overview

This report describes mitochondrial complex IV deficiency, nuclear type 5 (MC4DN5), previously called Leigh syndrome, French Canadian type. MC4DN5 exhibits autosomal recessive inheritance. The human gene implicated in this disease subtype is leucine rich pentatricopeptide repeat containing (LRPPRC), which is a nuclear gene targeted primarily to the mitochondria. It appears to play a role in RNA metabolism in both nuclei and mitochondria, and may play a role in the translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. There are two orthologous genes in Drosophila: Lrpprc2, for which classical mutations, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated, and bsf, for which RNAi-targeting constructs and alleles caused by insertional mutagenesis are available.

The human LRPPRC gene has not been introduced into flies.

Mutations of the fly Lrpprc2 gene were identified in a screen for essential genes (screened as mosaics) required for the maintenance of neurons in the fly visual system and were observed to result in decreased mitochondrial ATP production. Candidate genes have been assessed for genetic interactions with these mutations. Dmel\bsf and Dmel\Lrpprc2 appear to be partially redundant: homozygous loss-of-function mutations in either gene result in pupal lethality; the double mutant (homozygous) is lethal in the embryonic stage. Physical interactions have been described for both #bsf and Lrpprc2 and a single genetic interaction has been described for Lrpprc2; see below and in the bsf and Lrpprc2 gene reports.

[updated Feb. 2021 by FlyBase; FBrf0222196]

Disease Summary Information

Parent Disease Summary: Leigh syndrome

Symptoms and phenotype

Leigh syndrome is an early-onset progressive neurodegenerative disorder; clinical symptoms depend on which areas of the central nervous system are involved. [from MIM:256000; 2016.01.06]

(OMIM, 2013-)

The symptoms of Leigh syndrome usually begin between the ages of three months and two years. Symptoms are associated with progressive neurological deterioration and may include loss of previously acquired motor skills, loss of appetite, vomiting, irritability, and/or seizure activity. [from NORD, Leigh Syndrome; 2016.08.12]

(FlyBase Curators, 2013-)

Parent Disease Summary: mitochondrial complex IV deficiency, nuclear type

Symptoms and phenotype

Mitochondrial complex IV deficiency (cytochrome c oxidase deficiency) is clinically heterogeneous, ranging from isolated myopathy to severe multisystem disease, with onset from infancy to adulthood. [from MIM:220110; 2016.08.12]

(OMIM, 2013-)

Specific Disease Summary: mitochondrial complex IV deficiency, nuclear type 5

OMIM report

[MITOCHONDRIAL COMPLEX IV DEFICIENCY, NUCLEAR TYPE 5; MC4DN5](https://omim.org/entry/220111)

Human gene(s) implicated

[LEUCINE-RICH PPR MOTIF-CONTAINING PROTEIN; LRPPRC](https://omim.org/entry/607544)

Symptoms and phenotype

This type of Leigh syndrome is a severe neurologic disorder with onset in infancy. Features include delayed psychomotor development, mental retardation, mild dysmorphic facial features, hypotonia, ataxia, and the development of lesions in the brainstem and basal ganglia. Affected individuals tend to have episodic metabolic and/or neurologic crises in early childhood, which often lead to early death (summary by Debray et al., 2011; pubmed:21266382). [from MIM:220111; 2016.08.02]

(OMIM, 2013-)

Genetics

The French Canadian type of Leigh syndrome is caused by homozygous or compound heterozygous mutation in the LRPPRC gene; autosomal recessive. [from MIM:220111; 2016.08.02]

(OMIM, 2013-)

Cellular phenotype and pathology

Molecular information

The LRPPRC protein localizes primarily to mitochondria and is predicted to have an N-terminal mitochondrial targeting sequence. Its precise role is unknown; appears to play a role in RNA metabolism in both nuclei and mitochondria. Plays a role in translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. [Gene Cards, LRPPRC; 2016.08.02]

(FlyBase Curators, 2013-)

LRPPRC (leucine-rich PPR motif-containing protein) acts as part of a large protein complex that regulates posttranscriptional gene expression in mitochondria (Sasarman et al., 2010; pubmed:20200222). [from MIM:607544; 2016.08.02]

(OMIM, 2013-)

External links

Gene2Function (human gene): LRPPRC
Gene Cards: LRPPRC
MedlinePlus (condition): Leigh syndrome
MedlinePlus (condition): Cytochrome c oxidase deficiency
MedlinePlus (gene): LRPPRC
MARRVEL (human gene): LRPPRC
NCBI MedGen: Leigh syndrome, French Canadian type (LSFC)
NCBI (Entrez) gene: LRPPRC; leucine rich pentatricopeptide repeat containing
National Organization for Rare Disorders: Cytochrome C Oxidase Deficiency

Disease synonyms

COX deficiency, French-Canadian type

COX deficiency, French Canadian type

COX deficiency, Saguenay-Lac-Saint-Jean type

cytochrome C oxidase deficiency, French-Canadian type

cytochrome c oxidase deficiency, French Canadian type

Leigh syndrome, French-Canadian type

Leigh syndrome, French Canadian type

Leigh syndrome, LRPPRC-related

Leigh syndrome, Saguenay-Lac-Saint-Jean type

LSFC

MC4DN5

Related Diseases

Related human health report(s)

Leigh syndrome

mitochondrial complex IV deficiency, nuclear type

neuronopathy, distal hereditary motor, autosomal dominant 3

retinal degeneration, excessive endocytosis of rhodopsin

Related Specific Diseases

OMIM phenotypic series

Mitochondrial complex IV deficiency, nuclear-type

Disease

Associated Human gene(s)

Drosophila model

Human transgene in Drosophila

[MC4DN1](https://omim.org/entry/220110)

[SURF1](https://omim.org/entry/185620)

mitochondrial complex IV deficiency, nuclear type 1

[MC4DN2](https://omim.org/entry/604377)

[SCO2](https://omim.org/entry/604272)

mitochondrial complex IV deficiency, nuclear type 2

[MC4DN4](https://omim.org/entry/619048)

[SCO1](https://omim.org/entry/603644)

mitochondrial complex IV deficiency, nuclear type 4

[MC4DN5](https://omim.org/entry/220111)

[LRPPRC](https://omim.org/entry/607544)

mitochondrial complex IV deficiency, nuclear type 5

[MC4DN17](https://omim.org/entry/619061)

[COA8](https://omim.org/entry/616003)

mitochondrial complex IV deficiency, nuclear type 17

Ortholog Information

Human gene(s) in FlyBase

Human gene (HGNC)

Symbol / Name

LRPPRC; leucine rich pentatricopeptide repeat containing

D. melanogaster ortholog (based on DIOPT)

Dmel\Lrpprc2

(DIOPT, 2013-)

Dmel\bsf

(DIOPT, 2013-)

Dmel\bsf

(DIOPT, 2013-)

Comments on ortholog(s)

One to many: 1 human to 2 Drosophila.

Other mammalian ortholog(s) used

D. melanogaster Gene Information (2)

Dmel\Lrpprc2

Gene Snapshot

Leucine-rich pentatricopeptide repeat containing 2 (Lrpprc2) encodes an RNA-binding protein that forms a complex with the product of SLIRP2. It localizes to the mitochondrial matrix where it functions to coordinate mitochondrial translation. [Date last reviewed: 2019-03-14]

Molecular function (GO)

mRNA 3'-UTR binding

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Moderate-scoring ortholog of human LRPPRC (2 Drosophila to 1 human). Dmel\Lrpprc2 shares 24% identity and 42% similarity with human LRPPRC.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\bsf

Gene Snapshot

bicoid stability factor (bsf) encodes a member of the family of proteins containing the pentatricopeptide motif, an RNA binding domain. It is found in the cytoplasm, where it functions in mRNA stability and post-transcriptional control of gene expression, and in mitochondria, where it has multiple roles in gene expression. It acts at many stages of development, and is required for progression through oogenesis and viability. [Date last reviewed: 2019-03-28]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

High-scoring ortholog of human LRPPRC (2 Drosophila to 1 human). Dmel\bsf shares 30% identity and 49% similarity with human LRPPRC.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (26 groups)

Lrpprc2

protein-protein

Interacting group

Assay

References

Lrpprc2 - BicD

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - bsf

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - btz

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - Cbp80

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - CG10418

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - CG13126

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - exu

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - qkr58E-3

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - Sf3b3

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - SLIRP2

experimental knowledge based, anti tag coimmunoprecipitation, peptide massfingerprinting

(Baggio et al., 2014, Guruharsha et al., 2011)

Lrpprc2 - Syp

experimental knowledge based

(Guruharsha et al., 2011)

Lrpprc2 - Upf1

experimental knowledge based

(Guruharsha et al., 2011)

bsf

protein-protein

Interacting group

Assay

References

bsf - btz

experimental knowledge based

(Guruharsha et al., 2011)

bsf - Cbp80

experimental knowledge based

(Guruharsha et al., 2011)

bsf - CG13126

experimental knowledge based

(Guruharsha et al., 2011)

bsf - ClpX

anti tag coimmunoprecipitation, western blot

(Matsushima et al., 2017)

bsf - exu

experimental knowledge based

(Guruharsha et al., 2011)

bsf - foxo

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

bsf - gig

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

bsf - Lrpprc2

experimental knowledge based

(Guruharsha et al., 2011)

bsf - p53

pull down, autoradiography

(Lunardi et al., 2010)

bsf - rictor

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

bsf - S6kII

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

bsf - sima

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

bsf - SLIRP2

experimental knowledge based

(Guruharsha et al., 2011)

bsf - Tsc1

anti tag coimmunoprecipitation, Identification by mass spectrometry

(Vinayagam et al., 2016)

RNA-protein

Interacting group

Assay

References

bsf - osk

pull down, western blot

(Ryu and Macdonald, 2015)

Alleles Reported to Model Human Disease (Disease Ontology) (2 alleles)

Lrpprc2

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

Lrpprc2^A

model of Leigh disease

CEA

(Jaiswal et al., 2015)

model of French Canadian Leigh disease

CEA

(Cheramangalam et al., 2023)

Lrpprc2^E

model of Leigh disease

CEA

(Jaiswal et al., 2015)

model of French Canadian Leigh disease

CEA

(Cheramangalam et al., 2023)

Modifiers Based on Experimental Evidence ( 1 )

Allele

Disease

Interaction

References

Lrpprc2^A

model of Leigh disease

is ameliorated by Vps35^UAS.Tag:HA

(Jaiswal et al., 2015)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Genes involved in mitochondrial complex deficiency diseases

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

Lrpprc2^GD6368

P{GD6368}

w¹¹¹⁸; P{GD6368}v42899

y¹ sc^* v¹ sev²¹; P{TRiP.HMC06225}attP2/TM3, Sb¹

bsf^GD12587

P{GD12587}

w¹¹¹⁸; P{GD12587}v22837

bsf^JF01529

P{TRiP.JF01529}

y¹ v¹; P{TRiP.JF01529}attP2

bsf^JF01562

P{TRiP.JF01562}

y¹ v¹; P{TRiP.JF01562}attP2

bsf^HMS01022

P{TRiP.HMS01022}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01022}attP2

w¹¹¹⁸; P{GD12587}v22837

bsf^JF01529

P{TRiP.JF01529}

y¹ v¹; P{TRiP.JF01529}attP2

bsf^JF01562

P{TRiP.JF01562}

y¹ v¹; P{TRiP.JF01562}attP2

bsf^HMS01022

P{TRiP.HMS01022}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS01022}attP2

bsf^NIG.10302R

P{NIG.10302R}

P{NIG.10302R}1

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

Lrpprc2^A

ethyl methanesulfonate

y¹ Lrpprc2^A w^* P{neoFRT}19A/FM7c, P{GAL4-Kr.C}DC1, P{UAS-GFP.S65T}DC5, sn⁺

Lrpprc2^E

ethyl methanesulfonate

y¹ Lrpprc2^E w^* P{neoFRT}19A/FM7c, P{GAL4-Kr.C}DC1, P{UAS-GFP.S65T}DC5, sn⁺

bsf^SH1181

amorphic allele - molecular evidence

P-element activity

w^*; P{lacW}bsf^SH1181 P{neoFRT}40A/CyO

References (9)

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