Alternative titles; symbols
HGNC Approved Gene Symbol: CUL7
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:43,037,617-43,053,851 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | 3-M syndrome 1 | 273750 | Autosomal recessive | 3 |
By sequencing clones obtained from a size-fractionated human immature myeloid cell line cDNA library, Nomura et al. (1994) cloned CUL7, which they designated KIAA0076. The deduced 1,698-amino acid protein contains an ATP/GTP-binding site motif A and motifs found in mitochondrial energy transfer proteins. Northern blot analysis detected CUL7 expression in all tissues and cell lines tested except testis and small intestine.
By immunoprecipitating proteins that interacted with epitope-tagged ROC1 (RBX1; 603814) in human embryonic kidney cells, Dias et al. (2002) identified CUL7. The N-terminal half of CUL7 contains a 72-amino acid domain enriched in glycine and acidic residues that is similar to a corresponding region in HERC2 (605837). CUL7 also has a central DOC domain and a C-terminal cullin domain.
Dias et al. (2002) found that CUL7 assembled an SCF (see CUL1; 603134)-ROC1-like E3 ligase complex containing SKP1 (601434), CUL7, FBX29 (FBXW8; 609073), and ROC1 in human embryonic kidney cells. CUL7 specifically interacted with SKP1-FBX29, but not with SKP1 alone. CUL7 did not interact with SKP1-beta-TRCP2 (FBXW11; 605651) or SKP1-SKP2 (601436). Immunoprecipitated CUL7-ROC1 complexes converted monomeric ubiquitin into high molecular mass ubiquitin conjugates when incubated with E1 (see UBE1C; 603172) and UBC5C (UBE2D3; 602963).
Arai et al. (2003) found that mouse Cul7, which they designated p185, formed a specific SCF-like complex with Skp1, Fbx29, Rbx1, and Fap68 (GLMN; 601749). Cul7 associated with Skp1 in an Fbx29-dependent manner, and Fbx29 protein stability decreased in the absence of Cul7.
By PCR of a human/rodent hybrid panel, Nomura et al. (1994) mapped the CUL7 gene to chromosome 6.
The 3M syndrome (273750) is an autosomal recessive condition characterized by pre- and postnatal growth retardation, facial dysmorphism, large head circumference, and normal intelligence and endocrine function. Huber et al. (2005) used homozygosity mapping in 7 consanguineous families with 3M syndrome to show linkage of the underlying gene to a 3.84-Mb interval on 6p21.1. A search of human genome resources identified several putative disease-associated genes in the linkage region. Nine of these genes were excluded because no mutations were identified in them in 4 affected children of distinct ethnic origin by direct sequencing. The CUL7 gene also resided in the same region and was considered a good candidate because of data from the Cul7 gene-targeted mouse model. Direct sequencing of CUL7 in individuals with 3M syndrome detected 25 distinct mutations (see, e.g. 609577.0001-607577.0003). Of these, 19 predicted premature termination of translation and 6 were missense mutations. The patients with mutations in CUL7 included some who had been diagnosed with gloomy face syndrome (also known as Le Merrer syndrome), thus indicating that 'lumping' of these 2 conditions is justified.
In all 43 affected individuals with Yakut short stature syndrome, Maksimova et al. (2007) identified homozygosity for a founder mutation in the CUL7 gene (609577.0004).
Huber et al. (2009) identified homozygous or compound heterozygous CUL7 mutations (see, e.g., 609577.0005-609577.0007) in 23 of 33 patients with the 3M syndrome. Nineteen novel mutations throughout the gene were identified, including 1 case of paternal isodisomy of chromosome 6 encompassing a CUL7 mutation.
Arai et al. (2003) found that deletion of Cul7 in mice was neonatal lethal due to respiratory distress. A fraction of embryos were lost during embryonic days 10.5 to 12.5. At embryonic day 12.5, Cul7-null embryos were similar in size and weight to wildtype littermates, whereas mutant placentas were significantly reduced in size. Growth retardation of Cul7-null embryos became increasingly apparent relative to wildtype littermates in later gestational stages. Dermal and hypodermal hemorrhage was detected in mutant embryos at late gestational stage. Cul7-null placentas showed defects in differentiation of the trophoblast lineage with an abnormal vascular structure.
In 3 consanguineous Sri Lankan families with 3M syndrome-1 (3M1; 273750), Huber et al. (2005) found that affected individuals had an 4333C-T transition in exon 23 of the CUL7 gene, resulting in conversion of arg1445 to a stop codon in the cullin domain of the protein (R1445X). Additional studies indicated that the mutation rendered CUL7 deficient in recruiting ROC1 (603814) to the E3 ubiquitin ligase complex of which it is a part. A founder effect appeared clearly to be involved.
In 2 consanguineous Italian families with 3M syndrome-1 (3M1; 273750), Huber et al. (2005) found that affected individuals were homozygous for a 4391A-C transversion in exon 23 of the CUL7 gene, resulting in a his1464-to-pro (H1464P) substitution. Founder effect was presumably involved and was supported by the fact that the 2 families came from the same village.
In 5 consanguineous families, 4 from Tunisia and 1 from Algeria, with 3M syndrome-1 (3M1; 273750), Huber et al. (2005) identified an identical 2-bp deletion in exon 24 of the CUL7, resulting in a val1484-to-gly substitution and a frameshift leading to termination 68 codons downstream (Val1484GlyfsTer68). The presence of the same deletion in multiple consanguineous families suggested a founder effect in this region of North Africa. Huber et al. (2005) reported the deletion as 4449_4450delTG, but Huber et al. (2009) reported it as 4450_4451delTG. Also see 609577.0005.
In all 43 affected Yakut individuals with Yakut short stature syndrome (see 273750), Maksimova et al. (2007) identified a homozygous 1-bp insertion (4582_4583insT) in the CUL7 gene, resulting in a frameshift and premature termination. As the Yakuts are considered a population isolate, the mutation is likely due to a founder effect.
In 2 unrelated patients with 3M syndrome-1 (3M1; 273750), Huber et al. (2009) identified a homozygous 2-bp deletion (4449_4450delGT) in exon 24 of the CUL7 gene, resulting in a frameshift and premature termination after 68 codons downstream (Val1484GlyfsTer68). Both patients were born of consanguineous parents, from Algeria and Morocco, respectively. In an unrelated Italian patient, the authors identified compound heterozygosity for the 2-bp deletion and a C-to-A transversion (1570-3C-A; 609577.0007) in intron 6 of the CUL7 gene.
In 2 unrelated patients with 3M syndrome-1 (3M1; 273750), Huber et al. (2009) identified a homozygous 2-bp deletion (3379_3380delTG) in exon 18 of the CUL7 gene, resulting in a frameshift and premature termination. Both patients were born of consanguineous parents, from India and Pakistan, respectively.
For discussion of splice site mutation in intron 6 of the CUL7 gene (1570-3C-A) that was found in compound heterozygous state in a patient with 3M syndrome-1 (3M1; 273750) by Huber et al. (2009), see 609577.0005.
Arai, T., Kasper, J. S., Skaar, J. R., Ali, S. H., Takahashi, C., DeCaprio, J. A. Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis. Proc. Nat. Acad. Sci. 100: 9855-9860, 2003. [PubMed: 12904573] [Full Text: https://doi.org/10.1073/pnas.1733908100]
Dias, D. C., Dolios, G., Wang, R., Pan, Z.-Q. CUL7: A DOC domain-containing cullin selectively binds Skp1-Fbx29 to form an SCF-like complex. Proc. Nat. Acad. Sci. 99: 16601-16606, 2002. [PubMed: 12481031] [Full Text: https://doi.org/10.1073/pnas.252646399]
Huber, C., Delezoide, A.-L., Guimiot, F., Baumann, C., Malan, V., Le Merrer, M., Da Silva, D. B., Bonneau, D., Chatelain, P., Chu, C., Clark, R., Cox, H., and 23 others. A large-scale mutation search reveals genetic heterogeneity in 3M syndrome. Europ. J. Hum. Genet. 17: 395-400, 2009. [PubMed: 19225462] [Full Text: https://doi.org/10.1038/ejhg.2008.200]
Huber, C., Dias-Santagata, D., Glaser, A., O'Sullivan, J., Brauner, R., Wu, K., Xu, X., Pearce, K., Wang, R., Giovannucci Uzielli, M. L., Dagoneau, N., Chemaitilly, W., and 16 others. Identification of mutations in CUL7 in 3-M syndrome. Nature Genet. 37: 1119-1124, 2005. [PubMed: 16142236] [Full Text: https://doi.org/10.1038/ng1628]
Maksimova, N., Hara, K., Miyashia, A., Nikolaeva, I., Shiga, A., Nogovicina, A., Sukhomyasova, A., Argunov, V., Shvedova, A., Ikeuchi, T., Nishizawa, M., Kuwano, R., Onodera, O. Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia. J. Med. Genet. 44: 772-778, 2007. [PubMed: 17675530] [Full Text: https://doi.org/10.1136/jmg.2007.051979]
Nomura, N., Nagase, T., Miyajima, N., Sazuka, T., Tanaka, A., Sato, S., Seki, N., Kawarabayasi, Y., Ishikawa, K., Tabata, S. Prediction of the coding sequences of unidentified human genes. II. The coding sequences of 40 new genes (KIAA0041-KIAA0080) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res. 1: 223-229, 1994. [PubMed: 7584044] [Full Text: https://doi.org/10.1093/dnares/1.5.223]