Alternative titles; symbols
HGNC Approved Gene Symbol: SMC1A
SNOMEDCT: 55016009;
Cytogenetic location: Xp11.22 Genomic coordinates (GRCh38): X:53,374,149-53,422,728 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.22 | Cornelia de Lange syndrome 2 | 300590 | X-linked dominant | 3 |
| Developmental and epileptic encephalopathy 85, with or without midline brain defects | 301044 | X-linked dominant | 3 |
Eukaryotic sister chromatids remain connected from the time of synthesis until they are separated in anaphase. This cohesion depends on a complex of proteins known as cohesins. In vertebrates, unlike in yeast, the cohesins dissociate from chromosome arms earlier in M phase, during prophase. Small amounts of cohesin remain near the centromere until metaphase, with complete removal at the beginning of anaphase. Cohesin complexes contain SMC1, SCC1 (RAD21), SMC3 (606062), and either SA1 (STAG1; 604358) or SA2 (STAG2; 300826). The complexes, in turn, interact with PDS5 (see 613200), a protein implicated in chromosome cohesion, condensation, and recombination in yeast (summary by Sumara et al., 2000).
Genetic marker SB1.8 (DXS423E) was originally identified as a cross-reacting clone during the screening of a human lymphocyte cDNA library with an oligonucleotide probe corresponding to the CYBB (300481) gene, which maps to Xp21.1. Rocques et al. (1995) found that the DXS423E gene encodes a protein of 1,233 amino acids that is 30% identical to the essential yeast protein SMC1 (structural maintenance of chromosomes-1), which is required for the segregation of chromosomes at mitosis. Both the human protein, called SB1.8, and SMC1 contain an N-terminal NTP-binding site, a central coiled-coil region, and a C-terminal helix-loop-helix domain, and both have structural features in common with the force-generating proteins myosin and kinesin. SB1.8 also exhibits regions of homology and overall structural similarity to protein 115p of the prokaryote Mycoplasma hyorhinis.
In mouse embryos, Kruszka et al. (2019) found expression of the Smc1a gene in anterior neural folds, the neuroectoderm, and adjacent mesenchyme of the developing brain. The findings suggested a role in forebrain patterning.
In yeast, the cohesin complex is essential for sister chromatid cohesion during mitosis. The Smc1 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.
By yeast 2-hybrid screening of a human fetal brain expression cDNA library using the hinge domain of SMC1 as bait, followed by immunoprecipitation analysis, Patel and Ghiselli (2005) found that SMC1 interacted with hinderin (KIAA1328; 616480). Hinderin did not interact with SMC3. Interaction of hinderin with SMC1 precluded dimerization of SMC1 and SMC3.
Musio et al. (2005) demonstrated that RNA interference (RNAi) of SMC1 was sufficient to induce fragile site expression in normal human fibroblasts. They showed that aphidicolin treatment led to an increase in SMC1 synthesis, SMC1 phosphorylation via an ATR (601215)-dependent pathway, and enhanced double-stranded break induction as visualized by immunohistochemical studies with phosphorylated H2AX (601772). Discrete nuclear foci were absent or very rare after 1 or 2 hours exposure to aphidicolin and/or RNAi of SMC1 but became more numerous and distinct after 6 hours. Musio et al. (2005) proposed that fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of stalled DNA replication that lasted too long to be rescued via the ATR/SMC1 axis, whereas in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation.
Cohesin's Scc1, 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.
Kagey et al. (2010) reported that Mediator (see MED8, 607956) and cohesin physically and functionally connect the enhancers and core promoters of active genes in murine embryonic stem cells. Mediator, a transcriptional coactivator, forms a complex with cohesin, which can form rings that connect 2 DNA segments. The cohesin-loading factor NIPBL (608667) is associated with Mediator-cohesin complexes, providing a means to load cohesin at promoters. DNA looping is observed between the enhancers and promoters occupied by Mediator and cohesin. Mediator and cohesin co-occupy different promoters in different cells, thus generating cell type-specific DNA loops linked to the gene expression program of each cell.
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-MAU2 (614560), but not on topologic entrapment of DNA by cohesin (components include SMC3, 606062; SMC1A; STAG1, 604358; and 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.
Rocques et al. (1995) showed that the DXS423E gene maps to a cosmid contig that lies centromeric to the OATL2 locus (see 258870) at Xp11.2. Brown et al. (1995) showed that SMC1 escapes X-chromosome inactivation. SMC1 and XE169 (314690) were thought to define a new region in the proximal short arm of the X chromosome that escapes X inactivation. The corresponding gene in the mouse, Sb1.8, is located at the distal end of the X chromosome and is subject to X inactivation (Sultana et al., 1995).
Cornelia de Lange Syndrome 2
A female with a Cornelia de Lange syndrome (122470) phenotype carrying an apparently balanced X;8 translocation involving the Xp11.2 band, to which the SMC1L1 gene maps, was described by Egemen et al. (2005). The findings were consistent with the location of the SMC1L1 gene at Xp11.2 and the involvement of that gene in X-linked Cornelia de Lange syndrome-2 (CDLS2; 300590).
Musio et al. (2006) recruited 53 unrelated and 4 related individuals with a diagnosis of Cornelia de Lange syndrome, encompassing the entire spectrum of phenotypes. They found pathogenic NIPBL (608667) mutations in 24 of them, whereas the remaining 33 cases did not bear any NIPBL mutation. Of these 33 individuals, there was only 1 instance of familial occurrence, with 2 male sibs, their mother, and a first cousin affected. Involvement of the NIPBL gene was excluded in this family, but the affected individuals were found to carry a 3-bp deletion in the SMC1L1 gene (300040.0001). In addition, a sporadic case was found to have a de novo missense mutation in the SMC1L1 gene (300040.0002).
Deardorff et al. (2007) identified 14 additional SMC1A mutations in patients with a mild variant of Cornelia de Lange syndrome with predominant mental retardation. Analysis of the mutant SMC1A proteins indicated that they were likely to produce functional cohesin complexes; however, Deardorff et al. (2007) posited that they mutations may alter their chromosome binding dynamics. Ten of 14 SMC1A-mutation-positive individuals with CDLS identified by Deardorff et al. (2007) were female. Furthermore, their series included similarly affected male and female probands, implying an X-linked dominant mode of expression. Several males were rather mildly affected and no more severely affected than many of the SMC1A mutation-positive females. Since the SMC1A gene escapes X inactivation (Brown et al., 1995), it is likely that the mechanism in affected females is due to a dominant-negative effect of the altered protein and less likely that it is due to decreased protein levels or skewed X inactivation. Consistent with this dominant-negative effect on cohesin, Deardorff et al. (2007) described a single amino acid deletion mutation in the SMC3 gene underlying a variant Cornelia de Lange syndrome (606062.0001). The data indicated that SMC3 and SMC1A mutations contribute to approximately 5% of cases of Cornelia de Lange syndrome, result in a consistently mild phenotype with absence of major structural anomalies typically associated with CDLS, such as those of the limbs, and, in some instances, result in a phenotype that approaches that of apparently nonsyndromic mental retardation. Deardorff et al. (2007) suggested that it may be found that additional 'cohesinopathies' result from perturbation of the more than 15 additional components of this complex that had yet to be associated with human disorders.
Developmental and Epileptic Encephalopathy 85 with or without Midline Brain Defects
In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 with midline brain defects manifest as thin corpus callosum (DEE85; 301044), Lebrun et al. (2015) identified a de novo heterozygous splice site mutation in the SMC1A gene (300040.0007). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function.
In 2 unrelated girls with DEE85, Goldstein et al. (2015) identified de novo heterozygous frameshift mutations in the SMC1A gene (300040.0008 and 300040.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7) in 1 patient, but a random pattern in the other. Additional functional studies of the variants and studies of patient cells were not performed.
In 2 unrelated females with DEE85, Jansen et al. (2016) identified de novo heterozygous loss of function (LOF) mutations in the SMC1A gene (see, e.g., 300040.0010). The mutations were found by whole-genome sequencing. X-inactivation studies in 1 patient showed a random pattern, whereas it was skewed in the other patient (85:15). Additional functional studies were not performed. Jansen et al. (2016) concluded that the de novo LOF mutations in the SMC1A gene in females cause an abnormal dosage effect and that the resulting phenotype is distinct from CDLS2. The authors further suggested that LOF mutations in males may be embryonic lethal.
In 10 unrelated females with DEE85, Symonds et al. (2017) identified de novo heterozygous nonsense, frameshift, or splice site mutations in the SMC1A gene (see, e.g., 300040.0011-300040.0013). Functional studies of the variants were not performed. X-inactivation studies, performed in some patients, had variable results: some showed a random pattern, whereas others had a skewed pattern. Symonds et al. (2017) speculated that if SMC1A escapes X inactivation, then haploinsufficiency is unlikely to be the causative mechanism; rather, the authors postulated a dominant-negative effect. The findings also suggested that complete SMC1A deficiency is embryonic lethal, as no males with such mutations have been reported.
In 5 unrelated girls (patients 7-11) with DEE85 and variable midline brain defects, including holoprosencephaly (HPE), Kruszka et al. (2019) identified de novo heterozygous mutations in the SMC1A gene (see, e.g., 300040.0014 and 300040.0015). All mutations except 1 were nonsense, frameshift, or splice site mutations, suggesting a loss-of-function effect; there was 1 missense mutation. Functional studies of the variants and studies of patient cells were not performed. Knockdown of the SMC1A gene in human neural progenitor cells resulted in upregulation of GLI2 (165230), ZIC2 (603073), and SMAD3 (603109) gene expression. Although the significance of these findings was unclear, it demonstrated that loss of SMC1A perturbs the expression of genes involved in HPE. The patients were part of a cohort of 277 individuals with HPE as well as gathered through collaborative efforts such as GeneMatcher.
Musio et al. (2006) identified a 3-bp deletion in the SMC1L1 gene in hemizygous state in 2 brothers and a maternal first cousin from a family with X-linked Cornelia de Lange syndrome (300590). The mother of the 2 brothers was heterozygous for the mutation and mildly affected. The deletion involved the third nucleotide of codon 831 and the first 2 nucleotides of codon 832, leading to deletion of gln832 and an asp831-to-glu (D831E) substitution. The mutation was not identified in over 600 control chromosomes.
In a male patient with sporadic X-linked Cornelia de Lange syndrome (300590), Musio et al. (2006) identified hemizygosity for a 1478A-C transversion in the SMC1L1 gene, resulting in an glu493-to-ala (E493A) substitution. The mutation was not identified in over 400 control chromosomes.
Revenkova et al. (2009) showed that E493A-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents.
In a boy with a milder variant of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 15-bp deletion in the SMC1A gene, resulting in deletion of 5 amino acids (V58_R62del). Features of CDLS included arched eyebrows and synophrys, anteverted nostrils, long and featureless philtrum, thin lips, downturned corners of the mouth, hearing loss, cutis marmorata, small hands and feet, proximally set thumbs, clinodactyly of fifth finger, and hirsutism. The child had psychomotor delay but was in mainstream second grade schooling. He had mild pulmonic stenosis and gastroesophageal reflux.
In 2 sisters with a variant form of Cornelia de Lange syndrome (CDLS2; 300590), Deardorff et al. (2007) identified a 1487G-A transition in the SMC1A gene that resulted in an arg496-to-his substitution (R496H). Both had psychomotor delay and moderately severe mental retardation. One had pulmonic stenosis. Both had gastroesophageal reflux.
Revenkova et al. (2009) showed that R496H-mutant SMC1A affected the affinity of SMC hinge dimers for DNA. Mutated hinge dimers bound DNA with higher affinity than wildtype proteins. SMC1A-mutated Cornelia de Lange syndrome cell lines displayed genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents.
In a 6-year-old girl with Cornelia de Lange syndrome (CDLS2; 300590), Limongelli et al. (2010) identified a de novo heterozygous 2351T-C transition in exon 15 of the SMC1A gene, resulting in an ile784-to-thr (I784T) substitution in a highly conserved residue in the coiled-coil domain. She had pre- and postnatal growth retardation, developmental delay, characteristic facial features, and concentric left ventricular hypertrophic cardiomyopathy.
In a girl with a severe form of Cornelia de Lange syndrome-2 (CDLS2; 300590), Hoppman-Chaney et al. (2012) identified a de novo heterozygous 8.152-kb deletion encompassing exon 13 to intron 16 of the SMC1A gene, resulting in an in-frame deletion of 126 amino acids and insertion of 3 novel amino acids. The mutant mRNA was expressed, and Hoppman-Chaney et al. (2012) concluded that the mutant protein lacking the coiled-coil domain would act in a dominant-negative manner. The patient had dysmorphic facial features, microcephaly, poor growth, profound psychomotor retardation, holoprosencephaly, right hemihypertrophy, and mild distal limb anomalies. The patient was also mosaic for Turner syndrom, 45,X(7)/46,XX(23), which may have accounted for some additional features.
In a 7-year-old girl, born of unrelated Portuguese parents, with developmental and epileptic encephalopathy-85 and thin corpus callosum (DEE85; 301044), Lebrun et al. (2015) identified a de novo heterozygous G-to-T transversion (c.1911+1G-T) in intron 11 of the SMC1A gene, predicted to result in a splicing defect, frameshift, and premature termination (Thr638ValfsTer48). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Analysis of patient fibroblasts showed the presence of only the mutant transcript, which was significantly reduced compared to controls, suggesting nonsense-mediated mRNA decay and a loss of function. The patient had onset of infantile spasms associated with hypsarrhythmia on EEG within the first month of life. She also had microcephaly, dysmorphic facial features, and severe developmental delay. Brain imaging showed a thin corpus callosum.
In a 4-year-old girl (patient A) with developmental and epileptic encephalopathy-85 (DEE85; 301044) with possible thickening of the insular cortex on brain imaging, Goldstein et al. (2015) identified a de novo heterozygous 4-bp deletion (c.2853_2856delTCAG, NM_006306) in exon 18 of the SMC1A gene, resulting in a frameshift and premature termination (Ser951ArgfsTer12). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a skewed pattern (93:7), although it was not clear if the mutant allele was expressed. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of generalized tonic-clonic seizures at 4 months of age. The seizures became increasingly difficult to control, and she showed severe developmental regression and stagnation with inability to walk or speak.
In a 3-year-old girl (patient B) with developmental and epileptic encephalopathy-85 and slight thinning of the corpus callosum (DEE85; 301044), Goldstein et al. (2015) identified a de novo heterozygous 4-bp duplication (c.3549_3552dupGGCC, NM_006306) in exon 24 of the SMC1A gene, resulting in a frameshift and premature termination (Ile1185GlyfsTer23). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. X-inactivation studies in peripheral blood cells showed a random pattern. Additional functional studies of the variant and studies of patient cells were not performed. The patient had onset of tonic-clonic movements at 17 months of age following earlier global developmental delay.
In a 46-year-old woman (patient 1) with developmental and epileptic encephalopathy-85 (DEE85; 301044) without midline brain defects, Jansen et al. (2016) identified a de novo heterozygous 1-bp deletion (c.2364del, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination (Asn788LysfsTer10). The mutation was found by whole-genome sequencing and was predicted to result in nonsense-mediated mRNA decay and a loss of function. X-inactivation studies showed a random pattern. Additional functional studies were not performed. The patient had severe global developmental delay and onset of intractable seizures at 9 months of age.
In an 8-year-old girl (patient 4) with developmental and epileptic encephalopathy-85 (DEE85; 301044) without midline brain defects, Symonds et al. (2017) identified a de novo heterozygous c.2197G-T transversion (c.2197G-T, NM_006306) in the SMC1A gene, predicted to result in a glu733-to-ter (E733X) substitution. The mutation was found by exome sequencing. Functional studies of the variant and studies of patient cells were not performed, although X-inactivation studies showed a normal pattern. The patient had onset of focal and generalized seizures that were difficult to control at 5 months of age.
In 2 sisters (patients 8 and 9) with developmental and epileptic encephalopathy-85 (DEE85; 301044), Symonds et al. (2017) identified a de novo heterozygous 1-bp deletion (c.2477delA, NM_006306) in the SMC1A gene, predicted to result in a frameshift and premature termination. Functional studies of the variant and studies of patient cells were not performed. One sister had normal brain imaging and was less severely affected; she had onset of seizures at about 28 months of age. The other sister showed semilobar holoprosencephaly on brain imaging. She had onset of seizures in the first month of life and died at age 11 months. These findings demonstrated phenotypic variability even within the same family.
In a girl (patient 10) who died at age 9 years with developmental and epileptic encephalopathy-85 with abnormal corpus callosum (DEE85; 301044), Symonds et al. (2017) identified a de novo heterozygous c.3115C-T transition (c.3115C-T, NM_006306) in the SMC1A gene, predicted to result in a gln1039-to-ter (Q1039X) substitution. Functional studies of the variant and studies in patient cells were not performed, but X-inactivation studies showed a skewed ratio (76:24). The patient had onset of intractable tonic-clonic seizures at 2 months of age.
In a 6-year-old girl (patient 9) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; 301044), Kruszka et al. (2019) identified a de novo heterozygous c.2683C-G transversion (chrX.53,423,417G-C, GRCh37) in the SMC1A gene, resulting in an arg895-to-gly (R895G) substitution at a conserved residue in the second coiled-coil domain. Functional studies of the variant and studies of patient cells were not performed, but the authors postulated either a loss-of-function or a dominant-negative effect. The patient had early-onset seizures.
In a 3-year-old girl (patient 10) with developmental and epileptic encephalopathy-85 with semilobar holoprosencephaly (DEE85; 301044), Kruszka et al. (2019) identified a de novo heterozygous 1-bp deletion (c.2394delA; chrX.53,430,524delA) in the SMC1A gene, predicted to result in a frameshift and premature termination (Lys798AsnfsTer3). Functional studies of the variant and studies of patient cells were not performed. The patient had early-onset seizures.
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