MOCOS

protein-coding

molybdenum cofactor sulfurase

Gene summary

This gene encodes an enzyme that sulfurates the molybdenum cofactor which is required for activation of the xanthine dehydrogenase (XDH) and aldehyde oxidase (AO) enzymes. XDH catalyzes the conversion of hypoxanthine to uric acid via xanthine, as well as the conversion of allopurinol to oxypurinol, and pyrazinamide to 5-hydroxy pyrazinamide. Mutations in this gene cause the metabolic disorder classical xanthinuria type II which is characterized by the loss of XDH/XO and AO enzyme activity, decreased levels of uric acid in the urine, increased levels of xanthine and hypoxanthine in the serum and urine, formation of xanthine stones in the urinary tract, and myositis due to tissue deposition of xanthine. [provided by RefSeq, Apr 2017]

MANE transcript

NM_017947.4

Inheritance

ClinVar variants

P:46U:275B:109

Top phenotype

Xanthinuria, type II

gnomAD constraint

pLI —, LoF o/e 0.86

Max pathogenic AF

—

Genomic locus

chr18:36,187,497-36,272,157

External References & Databases

Ensembl (ENSG00000075643)

Transcript & Mutation Effects

hg38 • Region Span ~84.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

xanthinuria type IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011346

Submitter: Labcorp Genetics (formerly Invitae)

xanthinuria type IISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011346

Submitter: PanelApp Australia

xanthinuria type IIDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011346

Submitter: ClinGen

MOCOS was first reported in relation to autosomal recessive xanthinuria type II in 2001 (Ichida et al., PMID: 11302742). Xanthinuria type II is characterized by elevated xanthine/hypoxanthine in the urine and serum, and simultaneous low or undetectable levels of uric acid. This is due to an inability to synthesize sulfurated molybdenum-cofactor, the enzymatic product of the MOCOS enzyme, which is necessary for the activity of both xanthine oxidase and aldehyde oxidase. Xanthine oxidase is required for converting xanthine/hypoxanthine into uric acid. Many affected individuals remain asymptomatic, though ~40% develop urolithiasis, and ~5-10% experience non-specific stomach and/or muscle pain (PMID:25370766). Eight variants (five missense, one nonsense, two frameshift) that have been reported in eight probands in five publications (PMID: 11302742, 14624414, 17368066, 29935280, 34356852) are included in this curation. This gene-disease relationship is further supported by segregation evidence from two large families with multiple affected siblings (PMID: 17368066, 34356852). The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by expression studies, in vitro functional assays, and an animal model (PMID: 33017596, 16127175, 35372998). The MOCOS gene is most highly expressed in the liver and small intestine, which are the major sites of xanthine oxidase activity. Complete knock-out of the homologous gene in mice fully recapitulates the phenotypes observed in human patients, while also inducing late embryonic/perinatal lethality, failure to thrive, and early mortality that has not been observed in humans. In summary, MOCOS is definitively associated with autosomal recessive xanthinuria type II. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on 8/12/2022 (SOP Version 9).

xanthinuria type IISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011346

Submitter: Orphanet

Clinical Genomic Database (CGD)

Xanthinuria, type IIAR

Manifestation: Biochemical; Musculoskeletal; Renal

Intervention: Biochemical; Renal

Rationale: Most individuals are described as asymptomatic, but xanthine deposition can lead to myositis, urinary tract calculi, and acute renal failure and dietary measures (eg, purine restricted, increased fluid intake) and medical measures (eg, allopurinol) may be beneficial

Refs: 11302742; 14624414; 17368066; 25967871

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MOCOS variants in ClinVar

6 Conditions Cataloged

Xanthinuria type IITotal: 393

not specifiedTotal: 135

not providedTotal: 60

MOCOS-related disorderTotal: 39

Autism spectrum disorderTotal: 1

Primary hyperoxaluriaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017947.4. 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			4 clinvar	83 clinvar	2 clinvar	89
missense	1 clinvar	2 clinvar	263 clinvar	22 clinvar	2 clinvar	290
nonsense	4 clinvar	8 clinvar	3 clinvar			15
start loss						0
frameshift	8 clinvar	13 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)		10 clinvar	4 clinvar			14
Total	13	33	275	105	4	430

Highest pathogenic variant AF is 0.00080680044

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017947.4	RefSeq	NP_060417.4	15	MANE Select
ENST00000261326.6	Ensembl	ENSP00000261326.4	15	MANE Select
ENST00000880901.1	Ensembl	ENSP00000550960.1	15	Standard
ENST00000880901.2	Ensembl	ENSP00000550960.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Folate biosynthesis - Homo sapiens (human)
Metabolism
Molybdenum cofactor biosynthesis
Metabolism of water-soluble vitamins and cofactors
Metabolism of vitamins and cofactors

Biological Process

Mo-molybdopterin cofactor biosynthetic process
molybdopterin cofactor biosynthetic process
molybdopterin cofactor metabolic process

Molecular Function

protein binding
Mo-molybdopterin cofactor sulfurase activity
lyase activity
molybdenum ion binding
pyridoxal phosphate binding

Cellular Component

cellular_component
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261326
Coding exons: 15
Length: 84639
Individuals with no LoFs: 125434
Homozygous LoFs: 0
Heterozygous LoFs: 314
Defined: 125748
p: 0.00125

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.450	503	475	1.06	0.0000276	5797
Missense (PolyPhen)		178	175.36	1.015		2170
Synonymous	-0.170	191	188	1.02	0.0000111	1784
Loss of Function	0.795	32	37.2	0.859	0.00000181	447

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.0011	0.0011	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.0014	0.0014	notable
South Asian	0.0031	0.0030	notable
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sulfurates the molybdenum cofactor. Sulfation of molybdenum is essential for xanthine dehydrogenase (XDH) and aldehyde oxidase (ADO) enzymes in which molybdenum cofactor is liganded by 1 oxygen and 1 sulfur atom in active form. In vitro, the C-terminal domain is able to reduce N-hydroxylated prodrugs, such as benzamidoxime. {ECO:0000255|HAMAP-Rule:MF_03050, ECO:0000269|PubMed:16973608}.;
Disease: DISEASE: Xanthinuria 2 (XAN2) [MIM:603592]: A disorder characterized by excretion of very large amounts of xanthine in the urine and a tendency to form xanthine stones. Uric acid is strikingly diminished in serum and urine. In addition, XAN2 patients cannot metabolize allopurinol into oxypurinol due to dual deficiency of xanthine dehydrogenase and aldehyde oxidase. {ECO:0000269|PubMed:11302742, ECO:0000269|PubMed:14624414, ECO:0000269|PubMed:17368066, ECO:0000269|Ref.12}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.151

Intolerance Scores

LoFtool: 0.337
RVIS EVS: 1.72
RVIS percentile EVS: 96.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.201

Gene Damage Prediction

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