MRPL44

protein-coding

mitochondrial ribosomal protein L44, the group of Large subunit mitochondrial ribosomal proteins|Mitochondrial ribosomal proteins

Gene summary

Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. [provided by RefSeq, Jul 2008]

MANE transcript

NM_022915.5

Inheritance

ClinVar variants

P:8U:87B:50

Top phenotype

Combined oxidative phosphorylation deficiency 16

gnomAD constraint

pLI —, LoF o/e 1.05

Max pathogenic AF

—

Genomic locus

chr2:223,957,463-223,967,714

External References & Databases

Ensembl (ENSG00000135900)

Transcript & Mutation Effects

hg38 • Region Span ~10.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MRPL44* and autosomal recessive primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 7, 2022. The MRPL44 gene encodes mitochondrial ribosomal protein L44, which is a component of the large subunit (39S) of the mitochondrial ribosome. The *MRPL44 *gene was first reported in relation to primary mitochondrial disease in 2013 (PMID: 23315540). While various names have been given to the constellation of features seen in those with *MRPL44*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *MRPL44* phenotype has been lumped into one disease entity according to the ClinGen Lumping and Splitting Framework. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included four unique variants (3 missense, 1 frameshift) identified in six unrelated cases from four publications (PMIDs: 23315540, 25797485, 34140213, 33742325). The mechanism of pathogenicity appears to be loss of function. Of note, the c.467T>G, p.Leu156Arg variant has been identified in every case reported to date and may be a founder variant in the European population, although this has not been confirmed. This gene-disease relationship is also supported by a biochemical function (mitochondrial translation) shared with other genes associated with primary mitochondrial disease, functional alteration studies in patient cells showing impaired synthesis of mitochondrial proteins, and rescue of the mitochondrial protein levels and large mitochondrial ribosomal subunit assembly in patient cells following expression of the wild type protein (PMIDs: 33340416, 33742325, 23315540). In summary, there is definitive evidence to support the relationship between *MRPL44* and primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 7, 2022 (SOP Version 9).

infantile hypertrophic cardiomyopathy due to MRPL44 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014162

Submitter: PanelApp Australia

infantile hypertrophic cardiomyopathy due to MRPL44 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014162

Submitter: Labcorp Genetics (formerly Invitae)

infantile hypertrophic cardiomyopathy due to MRPL44 deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014162

Submitter: Orphanet

infantile hypertrophic cardiomyopathy due to MRPL44 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014162

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 16AR

Manifestation: Biochemical; Cardiovascular; Gastrointestinal; Musculoskeletal

Intervention: Cardiovascular

Rationale: Individuals have been reported as teenagers with hypertrophic cardiomyopathy (as well as with infantile-onset hyptertrophic cardiomyopathy), and surveillance for cardiomyopathy (eg, with echocardiography/electrocardiography) may allow early detection and medical treatment of disease manifestations

Refs: 23315540

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MRPL44 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 115

Inborn genetic diseasesTotal: 50

not specifiedTotal: 27

Infantile hypertrophic cardiomyopathy due to MRPL44 deficiencyTotal: 8

MRPL44-related disorderTotal: 4

MRPL44-related disordersTotal: 3

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1Total: 1

Mitochondrial complex IV deficiency, nuclear type 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022915.5. 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				42 clinvar	1 clinvar	43
missense		3 clinvar	78 clinvar	6 clinvar	1 clinvar	88
nonsense	1 clinvar	1 clinvar	3 clinvar			5
start loss		1 clinvar				1
frameshift	1 clinvar	1 clinvar	4 clinvar			6
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	2	6	87	48	2	145

Highest pathogenic variant AF is 0.00033827193

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022915.5	RefSeq	NP_075066.1	4	MANE Select
ENST00000258383.4	Ensembl	ENSP00000258383.3	4	MANE Select
ENST00000925223.1	Ensembl	ENSP00000595282.1	4	Standard
ENST00000977677.1	Ensembl	ENSP00000647494.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Mitochondrial translation initiation
Translation
Metabolism of proteins
Mitochondrial translation elongation
Mitochondrial translation termination

Biological Process

RNA processing
production of siRNA involved in RNA interference
primary miRNA processing
pre-miRNA processing
mitochondrial translational elongation

Molecular Function

RNA binding
double-stranded RNA binding
ribonuclease III activity
protein binding

Cellular Component

nucleus
mitochondrion
mitochondrial inner membrane
mitochondrial large ribosomal subunit
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000258383
Coding exons: 4
Length: 10311
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0785	177	180	0.984	0.00000874	2138
Missense (PolyPhen)		47	57.584	0.81619		611
Synonymous	0.206	68	70.2	0.969	0.00000350	673
Loss of Function	-0.162	13	12.4	1.05	5.21e-7	162

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.00046	0.00046	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the 39S subunit of mitochondrial ribosome. May have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome. {ECO:0000269|PubMed:23315540}.;
Disease: DISEASE: Combined oxidative phosphorylation deficiency 16 (COXPD16) [MIM:615395]: An autosomal recessive, mitochondrial disorder characterized by hypertrophic cardiomyopathy, liver steatosis, and decreased levels of mitochondrial complexes I and IV in heart and skeletal muscle. {ECO:0000269|PubMed:23315540}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.815
RVIS EVS: -0.27
RVIS percentile EVS: 34.6

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.894

Gene Damage Prediction

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