FXN

protein-coding

frataxin, the group of Mitochondrial iron-sulfur assembly components

Gene summary

This nuclear gene encodes a mitochondrial protein which belongs to the FRATAXIN family. The protein functions in regulating mitochondrial iron transport and respiration. The expansion of intronic trinucleotide repeat GAA from 8-33 repeats to >90 repeats results in Friedreich ataxia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]

Previous symbols:

FRDA

MANE transcript

NM_000144.5

Inheritance

ClinVar variants

P:27U:57B:32

Top phenotype

Friedreich ataxia 1

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr9:69,035,751-69,079,076

External References & Databases

Ensembl (ENSG00000165060)

Transcript & Mutation Effects

hg38 • Region Span ~43.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Friedreich ataxiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009245

Submitter: Orphanet

Friedreich ataxiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100339

Submitter: ClinGen

The FXN gene is associated with Friedreich ataxia, the most common form of inherited ataxia (Burk 2017, PMID: 28405347; Payne and Wagner 2012, PMID: 22764179). Friedreich ataxia is an autosomal recessive disorder characterized by progressive muscle weakness and ataxia, dysarthria, scoliosis, and cardiomyopathy. Homozygous inheritance of a GAA trinucleotide expansion within intron 1 of FXN accounts for 95% of Friedrich ataxia cases, while 5% of cases are due to compound heterozygous mutations including missense and nonsense mutations in FXN on one allele and the GAA trinucleotide repeat on the second allele (Burk 2017; PMID: 28405347; Delatycki 2000, PMID: 10633128). Friedreich ataxia was first described in 1863, by Nikolaus Friedreich, but it was not until 1996 that Campuzano and colleagues (PMID: 8596916) identified FXN as the causative gene responsible for Friedreich ataxia (Schulz 2013, PMID: 24024236). Many more cases are reported in the literature but the maximum score for genetic evidence (12 pts) has already been reached. Of note, FXN is a gene that is highly conserved from bacteria to mammals, and haplotype analysis has revealed a common ancestor originating from the Franco-Cantabrian ice age refuge (reviewed in Burk 2017, PMID: 28405347). The mechanism for disease is loss of function, as the GAA trinucleotide expansion results in the loss of FXN transcript due to epigenetic regulation. Loss of FXN (frataxin) results in reduced iron homeostasis within mitochondria, and results in mitochondrial dysfunction. This gene-disease association is supported by the function of the gene product, animal models, and rescue experiments. In summary, FXN is definitively associated with Friedreich ataxia. This association has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Data on the occurrence of hypertrophic cardiomyopathy (HCM) or cardiomyopathy in individuals with Friedreich ataxia was collected by the Hypertrophic Cardiomyopathy Gene Curation Committee (subgroup of the Cardiovascular Working Group). Loss of FXN results in the development of cardiomyopathy in ~92% of patients with Friedreich ataxia, and for 60% of these individual’s heart failure is the primary cause of death within the third to fifth decade of life (Payne and Wagner 2012, PMID: 22764179). The cardiomyopathy involved in Friedreich ataxia includes left ventricular hypertrophy, impaired myocardial perfusion, and arrhythmias. The cardiac hypertrophy observed in Friedreich ataxia was noted to differ from hypertrophic cardiomyopathy, as it is caused by increased proliferation of dysfunctional mitochondria within the cardiomyocytes which can ultimately lead to a dilated left ventricle and reduced ejection fraction (Payne and Wagner 2012, PMID: 22764179; Payne and Perverill 2012; PMID: 22373590).

Friedreich ataxia 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100340

Submitter: Labcorp Genetics (formerly Invitae)

Friedreich ataxiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100339

Submitter: PanelApp Australia

Friedreich ataxia 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100340

Submitter: G2P

Clinical Genomic Database (CGD)

Friedreich ataxia 1AR

Manifestation: Cardiovascular; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Though frequently clinically recognizable, the majority of individuals have cardiomyopathy, and medications (eg, antiarrhythmics, medications for cardiac-failure, anticoagulants, and pacemaker insertion) may be beneficial; Heart transplantation has been described

Refs: 13872187; 5673214; 5533984; 4206197; 7272714; 6231891; 8057123; 7695235; 8596916; 8623752; 8815938; 8751856; 9150176; 9142000; 9245990; 9259271; 9539351; 10399865; 10543403; 10533031; 10500204; 11425956; 11843702; 11857753; 15539131; 19347027; 20301458; 21700145; 21570254; 22409940; 22522441; 22691228; 22752483; 22752493; 22764179; 23196337; 23242090

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FXN variants in ClinVar

10 Conditions Cataloged

not providedTotal: 65

Inborn genetic diseasesTotal: 43

not specifiedTotal: 28

Friedreich ataxia 1Total: 18

Friedreich ataxiaTotal: 7

FXN-related disorderTotal: 4

FXN-related disordersTotal: 3

Cardiovascular phenotypeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000144.5. 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			3 clinvar	20 clinvar	2 clinvar	25
missense	4 clinvar	4 clinvar	52 clinvar	7 clinvar	3 clinvar	70
nonsense	3 clinvar	1 clinvar				4
start loss	2 clinvar	1 clinvar				3
frameshift	4 clinvar	1 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	1 clinvar			8
Total	14	13	57	27	5	116

Highest pathogenic variant AF is 0.00004214801

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000144.5	RefSeq	NP_000135.2	5	MANE Select
ENST00000484259.3	Ensembl	ENSP00000419243.2	5	MANE Select
NM_181425.3	RefSeq	NP_852090.1	5	Standard
ENST00000377270.8	Ensembl	ENSP00000366482.4	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Porphyrin and chlorophyll metabolism - Homo sapiens (human)
Metabolism of proteins
HIF-2-alpha transcription factor network
Mitochondrial iron-sulfur cluster biogenesis
Metabolism

Biological Process

oxidative phosphorylation
heme biosynthetic process
ion transport
cellular iron ion homeostasis
mitochondrion organization

Molecular Function

ferroxidase activity
protein binding
ferrous iron binding
ferric iron binding
iron chaperone activity

Cellular Component

mitochondrion
mitochondrial matrix
cytosol
L-cysteine desulfurase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000377270
Coding exons: 5
Length: 64920
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.284	94	102	0.921	0.00000567	1321
Missense (PolyPhen)		28	35.664	0.7851		446
Synonymous	-0.336	48	45.1	1.06	0.00000282	432
Loss of Function	2.11	2	8.70	0.230	3.70e-7	114

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes the biosynthesis of heme and assembly and repair of iron-sulfur clusters by delivering Fe(2+) to proteins involved in these pathways. May play a role in the protection against iron-catalyzed oxidative stress through its ability to catalyze the oxidation of Fe(2+) to Fe(3+); the oligomeric form but not the monomeric form has in vitro ferroxidase activity. May be able to store large amounts of iron in the form of a ferrihydrite mineral by oligomerization; however, the physiological relevance is unsure as reports are conflicting and the function has only been shown using heterologous overexpression systems. Modulates the RNA-binding activity of ACO1. {ECO:0000269|PubMed:12785837, ECO:0000269|PubMed:15247478, ECO:0000269|PubMed:15641778, ECO:0000269|PubMed:16239244, ECO:0000269|PubMed:16608849, ECO:0000269|PubMed:20053667}.;
Disease: DISEASE: Friedreich ataxia (FRDA) [MIM:229300]: Autosomal recessive, progressive degenerative disease characterized by neurodegeneration and cardiomyopathy it is the most common inherited ataxia. The disorder is usually manifest before adolescence and is generally characterized by incoordination of limb movements, dysarthria, nystagmus, diminished or absent tendon reflexes, Babinski sign, impairment of position and vibratory senses, scoliosis, pes cavus, and hammer toe. In most patients, FRDA is due to GAA triplet repeat expansions in the first intron of the frataxin gene. But in some cases the disease is due to mutations in the coding region. {ECO:0000269|PubMed:10732799, ECO:0000269|PubMed:10874325, ECO:0000269|PubMed:19629184, ECO:0000269|PubMed:9150176, ECO:0000269|PubMed:9779809, ECO:0000269|PubMed:9989622, ECO:0000269|Ref.36, ECO:0000269|Ref.7, ECO:0000269|Ref.8}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.390

Intolerance Scores

LoFtool: 0.0158
RVIS EVS: 0.41
RVIS percentile EVS: 76.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.762

Gene Damage Prediction

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