CNNM4 cyclin and CBS domain divalent metal cation transport mediator 4 [Homo sapiens (human)] - Gene

Summary

Official Symbol: CNNM4provided by HGNC
Official Full Name: cyclin and CBS domain divalent metal cation transport mediator 4provided by HGNC
Primary source: HGNC:HGNC:105
See related: Ensembl:ENSG00000158158 MIM:607805
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: ACDP4
Summary: This gene encodes a member of the ancient conserved domain containing protein family. Members of this protein family contain a cyclin box motif and have structural similarity to the cyclins. The encoded protein may play a role in metal ion transport. Mutations in this gene are associated with Jalili syndrome which consists of cone-rod dystrophy and amelogenesis imperfecta. [provided by RefSeq, Feb 2010]
Expression: Broad expression in colon (RPKM 26.1), thyroid (RPKM 9.4) and 23 other tissues See more
Orthologs: mouse all
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Genomic context

Location:: 2q11.2

Exon count:: 11

Annotation release	Status	Assembly	Chr	Location
109.20210514	current	GRCh38.p13 (GCF_000001405.39)	2	NC_000002.12 (96760902..96811888)
105.20201022	previous assembly	GRCh37.p13 (GCF_000001405.25)	2	NC_000002.11 (97426639..97477611)

Chromosome 2 - NC_000002.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Genomic Sequence:

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Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.
Title: Expanding the genotypic spectrum of Jalili syndrome: Novel CNNM4 variants and uniparental isodisomy in a north American patient cohort.
The novel identified variant in CNNM4 is the first report from the Pakistani population. Sequence analysis of CNNM4 revealed a novel missense variant (c.1220G>T, p.Arg407Leu) in exon-1 encoding cystathionine-beta-synthase (CBS) domain.
Title: A novel pathogenic missense variant in CNNM4 underlying Jalili syndrome: Insights from molecular dynamics simulations.
Jalili Syndrome is a rare cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI), We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants.
Title: Jalili Syndrome: Cross-sectional and Longitudinal Features of Seven Patients With Cone-Rod Dystrophy and Amelogenesis Imperfecta.
Here, we report the 2 first families with Jalili Syndrome in Brazil. Molecular analysis of the first family identified a previously described homozygous mutation (p.Leu324Pro) in exon 1 of CNNM4 gene. In the second family, affected patients demonstrated a compound heterozygous mutation in CNNM4, the p.Leu324Pro and the novel nonsense mutation p.Tyr581*.
Title: Report of two unrelated families with Jalili syndrome and a novel nonsense heterozygous mutation in CNNM4 gene.
Results identified linkage at chromosome 2p14-2q14 and found a homozygous mutation in the CNNM4 gene (p.R605X) causing Jalili syndrome. The truncated CNNM4 protein starting at R605 significantly increased the rate of apoptosis, and significantly increased the interaction between CNNM4 and IQCB1. This mutation may cause Jalili syndrome by a nonsense-mediated decay mechanism, affecting the function of IQCB1 and apoptosis.
Title: Identification of a mutation in CNNM4 by whole exome sequencing in an Amish family and functional link between CNNM4 and IQCB1.
Mutational analysis showed in all three brothers a novel likely pathogenic homozygous missense substitution in exon 1 (c.1076T>C, p.(Leu359Pro)) of CNNM4. Both parents were carriers for the variant.
Title: Co-occurrence of Jalili syndrome and muscular overgrowth.
We describe three siblings with clinical features of Jalili syndrome with a homozygous missense mutation in exon 4 of CNNM4, c.1781A>G (p.N594S).
Title: A new familial case of Jalili syndrome caused by a novel mutation in CNNM4.
These results suggest a new role of CNNM4 in sperm Ca(2+) homeostasis.
Title: The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and is essential for reproduction.
We identified a novel homozygous deleterious mutation in CNNM4 gene which causes Jalili syndrome.
Title: A novel mutation and variable phenotypic expression in a large consanguineous pedigree with Jalili syndrome.
used Sanger sequencing to analyze a large consanguineous family with three siblings affected with Jalili syndrome, suspected clinically after dental and ophthalmological examination. These patients are carrying a novel homozygous mutation in the splice site acceptor of intron 3 (c.1682-1G > C) in the CNNM4 gene
Title: Novel splice site mutation in CNNM4 gene in a family with Jalili syndrome.

Submit: New GeneRIF Correction See all GeneRIFs (19)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Jalili syndrome MedGen: C3495589 OMIM: 217080 GeneReviews: Not available	Compare labs
Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. GeneReviews: Not available

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

WI-20948 (e-PCR)
- UniSTS:28852

RH92382 (e-PCR)
- UniSTS:91584

AA859983 (e-PCR)
- UniSTS:261569

RH65684 (e-PCR)
- UniSTS:63962

D2S2187 (e-PCR), detects polymorphism
- UniSTS:49898

Homology

Homologs of the CNNM4 gene: The CNNM4 gene is conserved in dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 251 organisms have orthologs with human gene CNNM4
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables magnesium ion transmembrane transporter activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables sodium ion transmembrane transporter activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enables transmembrane transporter activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed

Process	Evidence Code	Pubs
involved_in enamel mineralization	IEA Inferred from Electronic Annotation more info
involved_in magnesium ion homeostasis	IBA Inferred from Biological aspect of Ancestor more info	PubMed
involved_in magnesium ion transmembrane transport	IEA Inferred from Electronic Annotation more info
involved_in magnesium ion transport	IBA Inferred from Biological aspect of Ancestor more info	PubMed
involved_in metal ion homeostasis	IDA Inferred from Direct Assay more info	PubMed
involved_in response to stimulus	IEA Inferred from Electronic Annotation more info
involved_in sodium ion transmembrane transport	IEA Inferred from Electronic Annotation more info
involved_in transport	IBA Inferred from Biological aspect of Ancestor more info	PubMed
involved_in visual perception	IEA Inferred from Electronic Annotation more info

Component	Evidence Code	Pubs
located_in basolateral plasma membrane	IEA Inferred from Electronic Annotation more info
located_in dendrite	IEA Inferred from Electronic Annotation more info
located_in integral component of membrane	IEA Inferred from Electronic Annotation more info
is_active_in intracellular membrane-bounded organelle	IBA Inferred from Biological aspect of Ancestor more info	PubMed
located_in neuronal cell body	IEA Inferred from Electronic Annotation more info
is_active_in plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
part_of protein-containing complex	IDA Inferred from Direct Assay more info	PubMed

General protein information

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Preferred Names: metal transporter CNNM4

Names: ancient conserved domain protein 4; ancient conserved domain-containing protein 4; cyclin-M4

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_016608.1 RefSeqGene

Range

5001..55973

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

NM_020184.4 → NP_064569.3 metal transporter CNNM4 precursor

See identical proteins and their annotated locations for NP_064569.3

Status: REVIEWED

Source sequence(s)

AB046812, BC063295

Consensus CDS

CCDS2024.2

UniProtKB/Swiss-Prot

Q6P4Q7

Related

ENSP00000366275.2, ENST00000377075.3

Conserved Domains (3) summary

COG0517
Location:373 → 500

CBS; CBS domain [Signal transduction mechanisms]

cd04590
Location:382 → 502

CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...

pfam01595
Location:196 → 358

DUF21; Domain of unknown function DUF21

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20210514

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000002.12 Reference GRCh38.p13 Primary Assembly

Range

96760902..96811888

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GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_005263914.4 → XP_005263971.1 metal transporter CNNM4 isoform X1

Conserved Domains (3) summary

COG0517
Location:373 → 500

CBS; CBS domain [Signal transduction mechanisms]

cd04590
Location:382 → 502

CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...

pfam01595
Location:196 → 358

DUF21; Domain of unknown function DUF21
XM_005263915.4 → XP_005263972.1 metal transporter CNNM4 isoform X2

Conserved Domains (3) summary

COG0517
Location:373 → 500

CBS; CBS domain [Signal transduction mechanisms]

cd04590
Location:382 → 502

CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...

pfam01595
Location:196 → 358

DUF21; Domain of unknown function DUF21
XM_011510955.3 → XP_011509257.1 metal transporter CNNM4 isoform X3

Conserved Domains (3) summary

COG0517
Location:373 → 500

CBS; CBS domain [Signal transduction mechanisms]

cd04590
Location:382 → 502

CBS_pair_CorC_HlyC_assoc; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains associated with the CorC_HlyC domain. CorC_HlyC is a transporter associated domain. This small domain is found in Na+/H+ antiporters, in proteins involved in ...

pfam01595
Location:196 → 358

DUF21; Domain of unknown function DUF21
XM_011510956.3 → XP_011509258.1 metal transporter CNNM4 isoform X4

Conserved Domains (2) summary

pfam01595
Location:196 → 358

DUF21; Domain of unknown function DUF21

cl15354
Location:382 → 474

CBS_pair; The CBS domain, named after human CBS, is a small domain originally identified in cystathionine beta-synthase and is subsequently found in a wide range of different proteins. CBS domains usually occur in tandem repeats. They associate to form a so-called ...
XM_017003799.1 → XP_016859288.1 metal transporter CNNM4 isoform X5