PYROXD1

protein-coding

pyridine nucleotide-disulphide oxidoreductase domain 1

Gene summary

This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

MANE transcript

NM_024854.5

Inheritance

ClinVar variants

P:31U:158B:73

Top phenotype

Myopathy, myofibrillar 8

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr12:21,437,615-21,471,250

External References & Databases

Ensembl (ENSG00000121350)

Transcript & Mutation Effects

hg38 • Region Span ~33.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myofibrillar myopathy 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014993

Submitter: G2P

myofibrillar myopathy 8DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014993

Submitter: ClinGen

PYROXD1 was first reported in relation to autosomal recessive myofibrillar myopathy 8 in 2016 (O'Grady GL, et al., 2016, PMID: 27745833). At least 7 unique variants (including missense, frameshift, and intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in four publications (PMIDs: 27745833, 31455395, 30345904, 30515627). Variants in this gene segregated with disease in six additional family members. This gene-disease relationship is supported by a Zebrafish knockdown model which is rescued by expression of human PYROXD1 (PMID: 27745833). Of note, this gene has been implicated in 12 families to date with a progressive course of disease and a predominant involvement of upper and lower limb muscles, however some exhibit a LGMD-like phenotype with childhood or adulthood disease onset while others are affected at birth, or in infancy, and manifest a more severe and complex clinical picture including scoliosis, nasal speech, joint hypermobility, contractures, rigid spine, pectus excavatum, and anomalies of the feet and hands. Overall and in view of the histological characteristics on biopsies as cores, central nuclei, and sarcoplasmic aggregates, PYROXD1-related myopathy can be considered as mixture of core myopathy, centronuclear myopathy, and myofibrillar myopathy which here have all been lumped into one disease entity. In summary, PYROXD1 is definitively associated with autosomal recessive myofibrillar myopathy 8.

myofibrillar myopathy 8MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014993

Submitter: Ambry Genetics

myofibrillar myopathy 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014993

Submitter: PanelApp Australia

myofibrillar myopathy 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014993

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Myopathy, myofibrillar 8AR

Manifestation: Cardiovascular; Musculoskeletal

Intervention: Cardiovascular

Rationale: Though not common, some individuals can have cardiovascular manifestations, and awareness can allow medical management

Refs: 27745833; 30345904; 30515627; 32037607; 33694278

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PYROXD1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 319

Inborn genetic diseasesTotal: 66

Myofibrillar myopathy 8Total: 18

PYROXD1-related disorderTotal: 11

not specifiedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024854.5. 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				61 clinvar	2 clinvar	63
missense	2 clinvar	1 clinvar	151 clinvar	10 clinvar		164
nonsense	2 clinvar		1 clinvar			3
start loss						0
frameshift	8 clinvar	6 clinvar	1 clinvar			15
splice donor/acceptor (+/-2bp)	2 clinvar	10 clinvar	5 clinvar			17
Total	14	17	158	71	2	262

Highest pathogenic variant AF is 0.00019409128

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 33 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024854.5	RefSeq	NP_079130.2	12	MANE Select
ENST00000240651.14	Ensembl	ENSP00000240651.9	12	MANE Select
NM_001350912.2	RefSeq	NP_001337841.1	10	Standard
NM_001350913.2	RefSeq	NP_001337842.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pyroxd1	Danio rerio	Structure: skeletal muscle Quality: broken abnormal

Gene / Model

Organism

Observed Phenotype

pyroxd1

Danio rerio

Structure: skeletal muscle

Quality: broken

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cellular response to oxidative stress
oxidation-reduction process

Molecular Function

protein binding
oxidoreductase activity

Cellular Component

nucleus
sarcomere

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000240651
Coding exons: 12
Length: 32752
Individuals with no LoFs: 125670
Homozygous LoFs: 0
Heterozygous LoFs: 78
Defined: 125748
p: 0.000310

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0969	252	256	0.983	0.0000123	3285
Missense (PolyPhen)		60	78.034	0.7689		989
Synonymous	0.0292	91	91.4	0.996	0.00000476	907
Loss of Function	1.69	17	26.4	0.644	0.00000140	345

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00045	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00037	0.00035	rare
South Asian	0.00028	0.00026	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in cellular response to oxidative stress. {ECO:0000269|PubMed:27745833}.;
Disease: DISEASE: Myopathy, myofibrillar, 8 (MFM8) [MIM:617258]: A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM8 is an autosomal recessive form, clinically characterized by slowly progressive symmetrical weakness affecting both proximal and distal muscles, with normal to moderately elevated creatine kinase. Mild facial weakness, a high palate, nasal speech, and swallowing difficulties are typical features, mild restrictive lung disease is common, and late-onset cardiac involvement may be present. {ECO:0000269|PubMed:27745833}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0932

Intolerance Scores

LoFtool: 0.499
RVIS EVS: -0.53
RVIS percentile EVS: 20.7

Essentials

Essential (CRISPR): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.712

Gene Damage Prediction

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