CD40LG |
- 3
Haplo
Score - 0
Triplo
Score
Gene Facts External Data Attribution
- HGNC Symbol
- CD40LG (HGNC:11935) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
- HGNC Name
- CD40 ligand
- Gene type
- protein-coding gene
- Locus type
- gene with protein product
- Previous symbols
- HIGM1, IMD3, TNFSF5
- Alias symbols
- CD40L, TRAP, gp39, hCD40L, CD154, CD40-L, HIGM1, T-BAM
- %HI
- 8.39(Read more about the DECIPHER Haploinsufficiency Index)
- pLI
- 0.72(Read more about gnomAD pLI score)
- LOEUF
- 0.56(Read more about gnomAD LOEUF score)
- Cytoband
- Xq26.3
- Genomic Coordinates
-
GRCh37/hg19: chrX:135730317-135742549 NCBI Ensembl UCSC GRCh38/hg38: chrX:136648158-136660390 NCBI Ensembl UCSC - MANE Select Transcript
- NM_000074.3 ENST00000370629.7 (Read more about MANE Select)
- Function
- Cytokine that acts as a ligand to CD40/TNFRSF5 (PubMed:1280226, PubMed:31331973). Costimulates T-cell proliferation and cytokine production (PubMed:8617933). Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation (PubMed:8617933). Induces the activation of NF-kappa-B (PubMed:15067037, PubMed:31331973). Induces the activation of kinases MAPK8 and PAK2 in T-cells (PubMed:15067037). ... (Source: Uniprot)
Dosage Sensitivity Summary (Gene)
Haploinsufficiency (HI) Score Details
- hyper-IgM syndrome type 1 Monarch
-
PUBMED:
22750225
Martinez et al. (2012) reported a maternally inherited exons 1-3 deletion of CD40LG gene in two brothers with recurrent otitis, bronchitis, pneumonias and diarrhea together with neutropenia since the earliest years of life. Both patients presented very low levels of IgG and undetectable of IgA and IgE, and none of the patients expressed CD40L even after T cell stimulation. They were both diagnosed with Hyper-IgM syndromes (HIGM). The mother who also carried a poly (p.G219R) on her second allele was healthy.
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PUBMED:
24768948
Tang et al. (2014) identified 10 distinct loss-of-function variants in CD40LG, including nonsense, as well as insertion and deletions which resulted in frame shift in 11 males with HIGM. Among them was a exon 1 deletion. All these patients showed no expression of CD40L on activated T cells. 7 out of 11 males inherited the variants from carrier mother.
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PUBMED:
16019685
Schuster et al. (2005) identified a deletion involving only the entire CD40LG gene in a 13 yro boy with HIGM, who also showed autoimmune retinopathy with retinal pigment epithelium (RPE) hypersensitivity. The younger brother of the patient was also affected by HIGM, however without any ophthalmological symptoms and it was not specified if he also carry the deletion.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.
Triplosensitivity (TS) Score Details
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PUBMED: 29499223
Le Coz et al. (2018) identified a 240 kb microduplication involving CD40LG, its regulatory elements and three other protein-coding genes in a 6-month old boy and his 25 yro mother. CD40L expression and CD40LG transcripts in the affected boy were twice that of unaffected relatives and he had coombs-positive hemolytic anemia that evolved into multi-lineage autoimmune cytopenias associated with massive splenomegaly. While his initial immunoglobulin A, G and M serum concentrations exceeded age-matched control ranges, IgM progressively declined until subject III.1 became selectively IgM deficient at five years old. His mother was diagnosed with mixed connective tissue disease and autoimmune thyroiditis, which resolved spontaneously during pregnancy 8 years later. Her CD40L level was indistinguishable from unaffected relatives, indicating random X-inactivation. The author speculated that the temporary reactivation of the CD40LG duplicated X-chromosome, with resultant functional trisomy, may have contributed to the development of her historical autoimmune disorders and the resumption of epigenetic control, to resolution of her disease.
The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.