Alternative titles; symbols
HGNC Approved Gene Symbol: SMC3
Cytogenetic location: 10q25.2 Genomic coordinates (GRCh38): 10:110,567,695-110,606,048 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.2 | Cornelia de Lange syndrome 3 | 610759 | Autosomal dominant | 3 |
The SMC3 gene encodes a subunit of the evolutionarily conserved multimeric cohesin complex, which has been implicated in a wide range of functions, including sister chromatid cohesion, DNA repair mechanisms, gene regulation, and maintenance of genome stability (summary by Gil-Rodriguez et al., 2015).
Proteoglycans are specialized glycoproteins with heterogeneous structures that are found in all connective tissues and on cell surfaces. SMC3, or bamacan (BAM), which was originally isolated from embryonic parietal yolk sac, is an abundant secreted chondroitin sulfate proteoglycan in basement membranes and an intracellular protein. See SCC1 (606462) and Sumara et al. (2000) for information on the role of SMC3 in cohesin association with and dissociation from chromosomes.
Using a yeast 2-hybrid screen of a B-cell cDNA library with SMAP (601836) as bait, followed by probing a brain cDNA library, Shimizu et al. (1998) obtained a cDNA encoding SMC3, which they termed HCAP. Sequence analysis predicted that the 1,217-amino acid HCAP protein is 98% identical to rat Cspg6 and is homologous to frog and fly Cap proteins. HCAP has a head-rod-tail organization, which is common in SMC family members. The head contains an NTP-binding motif and the tail has a DA box. Western blot analysis showed expression of an approximately 140-kD nuclear protein. GST-pull down analysis confirmed the specific interaction between SMAP and HCAP. Fluorescence microscopy demonstrated an association of HCAP with mitotic chromosomes. Coimmunoprecipitation analysis indicated that HCAP is associated with SMAP and KIF3A (604683)/KIF3B (603754) in the nucleus.
Using Northern blot analysis, Ghiselli et al. (1999) detected ubiquitous expression of a 4.2-kb Bam transcript in mouse, with highest levels in testis and brain, lower levels in muscle, heart, lung, kidney, colon, and thymus, and much lower levels in spleen, kidney, and liver. Ghiselli and Iozzo (2000) detected high levels of BAM expression in spontaneously transformed human and mouse colon carcinoma cells. They proposed that deregulated BAM/SMC3 expression may be directly linked to oncogenesis.
By genomic sequence analysis, Ghiselli et al. (1999) determined that the mouse Smc3 gene contains 31 exons and is driven by a promoter enriched in GC sequences and lacking TATA and CAAT boxes.
Gross (2015) mapped the SMC3 gene to chromosome 10q25.2 based on an alignment of the SMC3 sequence (GenBank AF020043) with the genomic sequence (GRCh38).
Ghiselli et al. (1999) mapped the mouse Smc3 gene to chromosome 19, in a region showing homology of synteny to human 10q25.
In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 (300040) and Smc3 subunits are rod-shaped molecules with globular ABC-like ATPases at one end and dimerization domains at the other, connected by long coiled coils. Smc1 and Smc3 associate to form V-shaped heterodimers. Their ATPase heads are thought to be bridged by a third subunit, Scc1, creating a huge triangular ring that can trap sister DNA molecules. Gruber et al. (2003) studied whether cohesin forms such rings in vivo. Proteolytic cleavage of Scc1 by separase at the onset of anaphase triggers its dissociation from chromosomes. The authors showed that N- and C-terminal Scc1 cleavage fragments remain connected due to their association with different heads of a single Smc1/Smc3 heterodimer. Cleavage of the Smc3 coiled-coil was sufficient to trigger cohesin release from chromosomes and loss of sister cohesion, consistent with a topologic association with chromatin.
Cohesin's Scc1 (606462), Smc1, and Smc3 subunits form a tripartite ring structure, and it had been proposed that cohesin holds sister DNA molecules together by trapping them inside its ring. To test this, Haering et al. (2008) used site-specific crosslinking to create chemical connections at the 3 interfaces between the 3 constituent polypeptides of the ring, thereby creating covalently closed cohesin rings. As predicted by the ring entrapment model, this procedure produced dimeric DNA-cohesin structures that are resistant to protein denaturation. Haering et al. (2008) concluded that cohesin rings concatenate individual sister minichromosome DNA molecules.
Rolef Ben-Shahar et al. (2008) identified spontaneous suppressors of the thermosensitive eco1-1 allele (see 609674) in budding yeast. An acetylation-mimicking mutation of a conserved lysine in cohesin's Smc3 subunit makes Eco1 dispensable for cell growth, and Rolef Ben-Shahar et al. (2008) showed that Smc3 is acetylated in an Eco1-dependent manner during DNA replication to promote sister chromatid cohesion. A second set of eco1-1 suppressors inactivate the budding yeast ortholog of the cohesin destabilizer Wapl (610754). Rolef Ben-Shahar et al. (2008) concluded that Eco1 modifies cohesin to stabilize sister chromatid cohesion in parallel with a cohesion establishment reaction that is in principle Eco1-independent.
Unal et al. (2008) found that in budding yeast, the head domain of the Smc3 protein subunit of cohesin is acetylated by the Eco1p protein acetyltransferase at 2 evolutionarily conserved residues, promoting the chromatin-bound cohesin to tether sister chromatids. Smc3 protein acetylation is induced in S phase after the chromatin loading of cohesin and is suppressed in G1 and G2/M.
Zhang et al. (2008) showed that acetylation of SMC3 by ESCO1 was required for S phase sister chromatid cohesion in human cells and in yeast. In HeLa cells, ESCO1 acetylated SMC3 on lys105 and lys106, and knockdown of ESCO1 expression via small interfering RNA significantly decreased SMC3 acetylation. Expression of a dominant-negative nonacetylatable SMC3 mutant in HEK293T cells permitted SMC3 incorporation into the cohesin complex, but it interfered with sister chromatid cohesion and resulted in scattered chromosomes and chromosome breakage. Zhang et al. (2008) concluded that ESCO1 is the major acetyltransferase required for SMC3 acetylation, and that SMC3 acetylation is required for sister chromatid cohesion and maintenance of genomic stability.
Through single-molecule analysis, Terret et al. (2009) demonstrated that a replication complex, the RFC-CTF18 clamp loader (see 613201), controls the velocity spacing and restart activity of replication forks in human cells and is required for robust acetylation of cohesin's SMC3 subunit and sister chromatid cohesion. Unexpectedly, Terret et al. (2009) discovered that cohesin acetylation itself is a central determinant of fork processivity, as slow-moving replication forks were found in cells lacking the Eco1-related acetyltransferases ESCO1 or ESCO2 (609353) (including those derived from Roberts syndrome (268300) patients, in whom ESCO2 is biallelically mutated), and in cells expressing a form of SMC3 that cannot be acetylated. This defect was a consequence of cohesin's hyperstable interaction with 2 regulatory cofactors, WAPL (610754) and PDS5A (613200); removal of either cofactor allowed forks to progress rapidly without ESCO1, ESCO2, or RFC-CTF18. Terret et al. (2009) concluded that their results showed a novel mechanism for clamp loader-dependent fork progression, mediated by the posttranslational modification and structural remodeling of the cohesin ring. Loss of this regulatory mechanism leads to the spontaneous accrual of DNA damage and may contribute to the abnormalities of the Roberts syndrome cohesinopathy.
Huis in 't Veld et al. (2014) found that the proposed DNA exit gate of cohesin is formed by interactions between SCC1 and the coiled-coil region of SMC3. Mutation of this interface abolished cohesin's ability to stably associate with chromatin and to mediate cohesion. Electron microscopy revealed that weakening of the SMC3-SCC1 interface resulted in opening of cohesin rings, as did proteolytic cleavage of SCC1. Huis in 't Veld et al. (2014) suggested that these open forms may resemble intermediate states of cohesin normally generated by the release factor WAPL and the protease separase (ESPL1; 604143), respectively.
Using biochemical reconstitution, Davidson et al. (2019) found that single human cohesin complexes form DNA loops symmetrically at rates up to 2.1 kilobase pairs per second. Loop formation and maintenance depend on cohesin's ATPase activity and on NIPBL (608667)-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3; SMC1A, 300040; STAG1, 604358; STAG2, 300826). During loop formation, cohesin and NIPBL-MAU2 reside at the base of loops, which indicates that they generate loops by extrusion. Davidson et al. (2019) concluded that their results showed that cohesin and NIPBL-MAU2 form an active holoenzyme that interacts with DNA either pseudotopologically or nontopologically to extrude genomic interphase DNA into loops.
Crystal Structure
Gligoris et al. (2014) showed that the N-terminal domain of yeast Scc1 (606462) contains 2 alpha-helices, forming a 4-helix bundle with the coiled coil emerging from the adenosine triphosphatase head of Smc3. Mutations affecting this interaction compromise cohesin's association with chromosomes. The interface is far from Smc3 residues, whose acetylation prevents cohesin's dissociation from chromosomes. Gligoris et al. (2014) concluded that cohesin complexes holding chromatids together in vivo do indeed have the configuration of heterotrimeric rings, and sister DNAs are entrapped within these.
Cornelia de Lange syndrome (CDLS; see 122470) is a multisystem developmental disorder including craniofacial dysmorphia, hirsutism, malformations of the upper limbs, and neurodevelopmental delay. Because mutations in the cohesin complex member NIPBL (608667) result in CDLS, Deardorff et al. (2007) screened 115 NIPBL mutation-negative individuals with sporadic or familial CDLS and probands with CDLS-variant phenotypes for mutations in the cohesin complex component genes SMC3 and SMC1A (300040). They found 1 mutation in SMC3 (606062.0001) in a patient with a milder CDLS phenotype (CDLS3; 610759). Structural analysis of the mutant SMC3 protein indicated that it was likely to produce a functional cohesin complex, but Deardorff et al. (2007) posited that the mutation may alter the chromosome binding dynamics of the protein. Additionally, the authors found 14 additional mutations in the SMC1A gene in patients with X-linked CDLS (CDLS2; 300590). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of CDLS, resulting in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, and in some instances, resulted in a phenotype that approached that of apparently nonsyndromic mental retardation.
In 5 unrelated patients with CDLS3, Ansari et al. (2014) identified 5 different heterozygous mutations in the SMC3 gene (see, e.g., 606062.0002 and 606062.0003). The mutations were shown to occur de novo in those with available parental DNA. Functional studies were not performed.
Gil-Rodriguez et al. (2015) identified heterozygous mutations in the SMC3 gene (see, e.g., 606062.0001; 606062.0004-606062.0008) in 10 unrelated patients with CDLS3. The mutations were shown to occur de novo in those with available parental DNA. The mutations were found either by gene panel sequencing or by exome sequencing, and none were found in 100 control alleles of publicly available databases. Functional studies were not performed. Based on their studies and previous reports, Gil-Rodriguez et al. (2015) estimated that SMC3 mutations account for about 1 to 2% of patients with features of CDLS.
In a male fetus with a severe form of CDLS3 with midline brain defects manifest as semilobar holoprosencephaly, Kruszka et al. (2019) identified a de novo heterozygous 15-bp in-frame deletion in the SMC3 gene (606062.0009). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database.
In a male with a mild variant form of Cornelia de Lange syndrome (CDLS3; 610759), Deardorff et al. (2007) found a 3-bp deletion in the SMC3 gene (1464_1466delAGA), resulting in deletion of glu488 (E488del). The mutation occurred in the junction of the N-terminal coiled-coil and the hinge domain, a region conserved from bacteria to human. Neither parent carried the mutation, indicating that it was a de novo event.
Revenkova et al. (2009) showed that E488del-mutant SMC3 affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins, and SMC3-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents.
Gil-Rodriguez et al. (2015) identified a de novo heterozygous E488del mutation in a boy with a moderate form of CDLS3. The mutation was found by exome sequencing; functional studies were not performed.
By gene panel sequencing, Ansari et al. (2014) identified a heterozygous phe47-to-leu (F47L) mutation in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; 610759). Gil-Rodriguez et al. (2015) reported that the mutation in this female patient with a mild form of CDLS3 was a c.139T-C transition in exon 4 of the SMC3 gene, resulting in an F47L substitution at a conserved residue in the N-terminal ATP-binding head domain. The mutation was not present in the mother; DNA from the father was not available. Functional studies were not performed.
By gene panel sequencing, Ansari et al. (2014) identified a 3-bp deletion (Thr1235del) in the SMC3 gene in a patient with Cornelia de Lange syndrome-3 (CDLS3; 610759); the patient was somatic mosaic for the mutation. Gil-Rodriguez et al. (2015) reported that the mutation in this female patient with a moderate form of the disorder was a de novo heterozygous in-frame 3-bp deletion (c.703_705del) in exon 9 of the SMC3 gene, resulting in deletion of the conserved residue Thr235 in the coiled-coil region. Functional studies were not performed.
In a boy with a mild form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.707G-C transversion in exon 9 of the SMC3 gene, resulting in an arg236-to-pro (R236P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. Functional studies were not performed.
In a boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1462G-A transition in exon 15 of the SMC3 gene, resulting in a glu488-to-lys (E488K) substitution at a conserved residue in the coiled-coil domain. The mutation was found by gene panel sequencing. Functional studies were not performed.
In a girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1964G-A transition in exon 19 of the SMC3 gene, resulting in a gly655-to-asp (G655D) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. Functional studies were not performed.
In a boy with a mild to moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.1997G-C transversion in exon 19 of the SMC3 gene, resulting in a gly666-to-ala (G666A) substitution at a conserved residue in the hinge domain. The mutation was found by gene panel sequencing. Functional studies were not performed.
In a girl with a moderate form of Cornelia de Lange syndrome-3 (CDLS3; 610759), Gil-Rodriguez et al. (2015) identified a de novo heterozygous c.2750A-C transversion in exon 24 of the SMC3 gene, resulting in a his917-to-pro (H917P) substitution at a conserved residue in the coiled-coil domain. The mutation was found by exome sequencing. Functional studies were not performed.
In a male fetus with a severe form of Cornelia de Lange syndrome-3 with midline brain defects manifest as semilobar holoprosencephaly (CDLS3; 610759), Kruszka et al. (2019) identified a de novo heterozygous 15-bp in-frame deletion (c.1138_1152del) (chr10.112,343,987del15, GRCh37) in the SMC3 gene, predicted to result in the deletion of 5 amino acids (Gly380_Gln384del). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; the patient was ascertained from a large cohort of over 277 patients with holoprosencephaly. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function (LOF). The authors noted that the SMC3 gene is intolerant to LOF mutations based on data from the gnomAD database.
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