NFU1

protein-coding

NFU1 iron-sulfur cluster scaffold, the group of Mitochondrial iron-sulfur assembly components

Gene summary

This gene encodes a protein that is localized to mitochondria and plays a critical role in iron-sulfur cluster biogenesis. The encoded protein assembles and transfers 4Fe-4S clusters to target apoproteins including succinate dehydrogenase and lipoic acid synthase. Mutations in this gene are a cause of multiple mitochondrial dysfunctions syndrome-1, and pseudogenes of this gene are located on the short arms of chromosomes 1 and 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:

HIRIP5

MANE transcript

NM_001002755.4

Inheritance

ClinVar variants

P:18U:69B:31

Top phenotype

Multiple mitochondrial dysfunctions syndrome 1; Spastic paraplegia 93, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr2:69,396,113-69,437,628

External References & Databases

Ensembl (ENSG00000169599)

Transcript & Mutation Effects

hg38 • Region Span ~41.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

multiple mitochondrial dysfunctions syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011582

Submitter: G2P

multiple mitochondrial dysfunctions syndrome 1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011582

Submitter: Orphanet

multiple mitochondrial dysfunctions syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011582

Submitter: PanelApp Australia

multiple mitochondrial dysfunctions syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011582

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *NFU1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of July 11, 2023. *NFU1* encodes a protein essential to the assembly of iron-sulfur (Fe-S) clusters. *NFU1* was first reported in relation to autosomal recessive primary mitochondrial disease in 2011 (PMID:21944046, although this case was first reported in 2001, PMID:11156534), in an infant who died at age one month due to respiratory failure in the setting of metabolic acidosis, hyperglycinemia and multiple organ failure. Tissue testing indicated a clear reduction in lipoate containing 2-oxoacid dehydrogenases (pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase) as well as defects in complexes I, II, and III which is characteristic of this Fe-S cluster defect. While various names have been given to the constellation of features seen in those with *NFU1*-related disease, pathogenic variants in this gene cause a primary mitochondrial disease. Therefore, the *NFU1* 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 six unique variants (two frameshift null variants, three missense variants, and one predicted missense variant resulting in aberrant splicing) in five probands from three publications (PMIDs: 22077971, 25918518, 25758857), although many additional cases (~35) are reported in the medical literature. The p.Gly208Cys variant appears to be a Basque founder variant. Affected individuals have a strikingly similar biochemical phenotype but variable severity of their clinical phenotype. Two general clinical phenotypes have been reported. One is an infantile onset, potentially fatal, lactic acidosis with leukoencephalopathy with or without pulmonary hypertension, optic atrophy, and/or cardiomyopathy. The second is an early childhood onset hereditary spastic paraplegia with leukoencephalopathy and regression. Affected individuals show a reduction in activities and amounts of lipoate containing enzymes as well as hyperglycinemia/hyperglycinuria (PMIDs: 22077971, 25918518, 25758857). This gene-disease association is also supported by functional implication given protein interaction with other genes involved in Fe-S cluster assembly or lipoylation (PMID: 33007329). HeLa cell models and yeast cell models replicating similar biochemical defects seen in patients (PMID: 22077971) and functional deficiencies seen in patient cells (PMID:36256512) were also included in scoring. In summary, there is definitive evidence to support the relationship between *NFU1* and primary mitochondrial disease. This has been repeatedly demonstrated and upheld over time, and no convincing evidence has emerged that contradicts this gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on July 11, 2023 (SOP Version 9).

multiple mitochondrial dysfunctions syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011582

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Multiple mitochondrial dysfunctions syndrome 1; Spastic paraplegia 93, autosomal recessiveAR

Manifestation: Biochemical; Cardiovascular; Musculoskeletal; Neurologic

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: 11156534; 21944046; 25758857; 32747156; 36256512

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NFU1 variants in ClinVar

6 Conditions Cataloged

Multiple mitochondrial dysfunctions syndrome 1Total: 105

not providedTotal: 64

Inborn genetic diseasesTotal: 29

not specifiedTotal: 22

Spastic paraplegia 93, autosomal recessiveTotal: 14

NFU1-related disorderTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001002755.4. 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	27 clinvar	1 clinvar	31
missense	7 clinvar	4 clinvar	62 clinvar	3 clinvar		76
nonsense		2 clinvar				2
start loss						0
frameshift	1 clinvar	2 clinvar	1 clinvar			4
splice donor/acceptor (+/-2bp)		2 clinvar	3 clinvar			5
Total	8	10	69	30	1	118

Highest pathogenic variant AF is 0.00007806865

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001002755.4	RefSeq	NP_001002755.1	8	MANE Select
ENST00000410022.7	Ensembl	ENSP00000387219.3	8	MANE Select
NM_001002756.2	RefSeq	NP_001002756.1	4	Standard
NM_001374284.1	RefSeq	NP_001361213.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

iron-sulfur cluster assembly
protein maturation by iron-sulfur cluster transfer

Molecular Function

iron ion binding
protein binding
4 iron, 4 sulfur cluster binding

Cellular Component

nucleus
nucleoplasm
mitochondrion
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000410022
Coding exons: 8
Length: 41879
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 43
Defined: 125747
p: 0.000171

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.370	123	135	0.910	0.00000623	1653
Missense (PolyPhen)		40	45.843	0.87254		604
Synonymous	0.598	42	47.2	0.889	0.00000222	473
Loss of Function	0.940	10	13.8	0.727	5.80e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00076	0.00074	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00012	rare
South Asian	0.00026	0.00026	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Iron-sulfur cluster scaffold protein which can assemble [4Fe-4S] clusters and deliver them to target proteins. {ECO:0000269|PubMed:12886008, ECO:0000269|PubMed:27818104, ECO:0000269|PubMed:28906594}.;
Disease: DISEASE: Multiple mitochondrial dysfunctions syndrome 1 (MMDS1) [MIM:605711]: A severe disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, hyperglycinemia and early death. Some patients show failure to thrive, pulmonary hypertension, hypotonia and irritability. Biochemical features include severe combined deficiency of the 2-oxoacid dehydrogenases, defective lipoic acid synthesis and reduction in activity of mitochondrial respiratory chain complexes. {ECO:0000269|PubMed:21944046, ECO:0000269|PubMed:22077971, ECO:0000269|PubMed:25918518, ECO:0000269|PubMed:28161430, ECO:0000269|PubMed:28906594}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.621
RVIS EVS: 0.42
RVIS percentile EVS: 76.81

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.900

Gene Damage Prediction

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