CCN4

Chr 8

cellular communication network factor 4

Also known as: WISP1, WISP1-OT1, WISP1-UT1, WISP1c, WISP1i, WISP1tc

NCBI Gene: 8840 ENSG00000104415 UniProt: O95388 OMIM: 603398

The CCN4 protein is a downstream regulator in the Wnt signaling pathway that promotes cell survival by attenuating p53-mediated apoptosis and upregulating anti-apoptotic proteins. Mutations in CCN4 cause autosomal recessive spondylomegaepiphyseal dysplasia with upper limb mesomelia, joint laxity, and distinctive facies, a skeletal dysplasia syndrome affecting bone and cartilage development. The gene shows low constraint to loss-of-function variation (pLI near 0), consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the WNT1 inducible signaling pathway (WISP) protein subfamily, which belongs to the connective tissue growth factor (CTGF) family. WNT1 is a member of a family of cysteine-rich, glycosylated signaling proteins that mediate diverse developmental processes. The CTGF family members are characterized by four conserved cysteine-rich domains: insulin-like growth factor-binding domain, von Willebrand factor type C module, thrombospondin domain and C-terminal cystine knot-like domain. This gene may be downstream in the WNT1 signaling pathway that is relevant to malignant transformation. It is expressed at a high level in fibroblast cells, and overexpressed in colon tumors. The encoded protein binds to decorin and biglycan, two members of a family of small leucine-rich proteoglycans present in the extracellular matrix of connective tissue, and possibly prevents the inhibitory activity of decorin and biglycan in tumor cell proliferation. It also attenuates p53-mediated apoptosis in response to DNA damage through activation of the Akt kinase. It is 83% identical to the mouse protein at the amino acid level. Multiple alternatively spliced transcript variants have been identified. [provided by RefSeq, Mar 2011]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.13

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.13LOEUF

pLI 0.000

Z-score 1.18

OE 0.69 (0.44–1.13)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.22Z-score

OE missense 0.96 (0.86–1.07)

236 obs / 245.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.69 (0.44–1.13)

0≤0.351.4

Missense OE?0.96 (0.86–1.07)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 12 / 17.3Missense obs/exp: 236 / 245.5Syn Z: -1.11

Background carrier burden — how many people carry a rare variant somewhere in CCN4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 73

547 rare PASS variants

Rare truncating (LoF)

1 in 2,500

67 rare PASS variants

Rare synonymous (reference)

1 in 120

183 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CCN4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 4,800
South Asian	~43k	1 in 53	1 in 650
Remaining (unassigned)	~30k	1 in 59	1 in 800
European (Finnish)	~27k	1 in 250	1 in 1,200
Admixed American	~22k	1 in 54	1 in 2,800
African / African American	~21k	1 in 84	1 in 1,100
East Asian	~20k	1 in 95	1 in 1,400
Ashkenazi Jewish	~13k	1 in 310	1 in 1,500
Middle Eastern	~2,884	1 in 63	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓