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SIN3 TRANSCRIPTION REGULATOR FAMILY MEMBER A; SIN3A

SIN3 TRANSCRIPTION REGULATOR FAMILY MEMBER A; SIN3A

Alternative titles; symbolsSIN3, YEAST, HOMOLOG OF, AHGNC Approved Gene Symbol: SIN3ACytogenetic location: 15q24.2 Genomic coordinates (GRCh38): 15:75,369,37...

Alternative titles; symbols

  • SIN3, YEAST, HOMOLOG OF, A

HGNC Approved Gene Symbol: SIN3A

Cytogenetic location: 15q24.2 Genomic coordinates (GRCh38): 15:75,369,378-75,455,818 (from NCBI)

▼ Description
Protein complexes containing SIN3A act as histone deacetylase (see HDAC1; 601241)-dependent corepressors. SIN3A contains multiple protein-protein interaction domains and serves as a scaffold on which the corepressor complex assembles (Fleischer et al., 2003).

▼ Cloning and Expression
Ayer et al. (1995) cloned mouse Sin3a. The deduced 1,219-amino acid protein contains 4 paired amphipathic helix (PAH) domains. Ayer et al. (1995) also identified an alternatively spliced isoform with a 9-amino acid insert near the C terminus. Sin3a shares significant homology with yeast Sin3 and mouse Sin3b (607777). The highest homology lies within the 4 PAH domains and between PAH3 and PAH4. Sin3a and Sin3b share less homology at their N termini.

Halleck et al. (1995) also cloned mouse Sin3a. They identified a nuclear localization sequence between PAH2 and PAH3, as well as a PEST motif, which mediates rapid protein degradation. Northern blot analysis detected a 5.0-kb transcript in all mouse tissues examined, with highest levels in lung and testis. Less-abundant transcripts of 2.4, 2.0, and 1.0 kb were detected in brain, liver, and kidney.

Witteveen et al. (2016) reported that human SIN3A mRNA is present prenatally in the ventricular zone of various cortical brain regions, where progenitor proliferation occurs. In the mouse, Sin3a was expressed at relatively high levels throughout brain development, increasing and decreasing at different time points in different regions. It was expressed in neurogenic regions and in cortical regions, where it localized to the nucleus of neurons, particularly in newborn neurons and proliferating neurons. Overall, the expression patterns became more restricted over time.

▼ Mapping
By in situ hybridization, Halleck et al. (1995) mapped the SIN3A gene to chromosome 15q24.

▼ Gene Function
By immunoprecipitation of in vitro translated proteins, Ayer et al. (1995) demonstrated direct interaction between mouse Sin3a and Mad (600021). Using mutation analysis, they mapped the interacting domains to PAH2 of Sin3a and to the N-terminal 25 amino acids of Mad, which contain a putative amphipathic alpha helix. Ayer et al. (1995) also determined that Sin3 formed ternary complexes in solution with Mad and Max (154950) and that the complex recognized the Mad-Max E box-binding site and repressed transcription of a reporter gene. They hypothesized that Mad-Max represses transcription by tethering the Sin3 proteins to DNA as corepressors.

Yu et al. (2000) demonstrated interaction between endogenous human SIN3A and the transcriptional repression domain of methyl-CpG-binding protein-2 (300005).

Zhang and Dufau (2002) presented evidence that a complex between SIN3A and HDACs repressed transcription of the gene encoding luteinizing hormone receptor (LHR; 152790). A multiprotein complex including HDAC1, HDAC2 (605164), and SIN3A was recruited to SP1 (189906) and SP3 (601804) sites of the LHR promoter and silenced SP1/SP3-driven LHR gene transcription. SIN3A interacted directly with both HDACs in the complex.

Fleischer et al. (2003) purified a SIN3A-containing complex of more than 500 kD from K562 human erythroleukemia cells. By microsequence analysis, they identified SAP180 (ARID4B; 609696), SAP130 (609697), SDS3 (608250), RbAp48 (RBBP4; 602923), SAP30 (603378), HDAC1, and HDAC2 as components of the complex. SAP180, SAP130, and SDS3 bound the central HDAC-interacting domain of SIN3A. SAP130 and SDS3 also bound sequences in the N-terminal half of SIN3A distinct from the HDAC-interacting domain. SIN3A and HDAC1 were required for transcriptional repression mediated by SAP180 and SAP130.

Using in vitro binding assays, Shiio et al. (2006) showed that mouse Sap25 (619230) bound Sin3a. Mutation analysis revealed that the interaction involved the C-terminal region of Sap25 containing an LxxLL motif and the PAH1 domain of Sin3a. Immunoprecipitation analysis in 293T cells confirmed in vivo interaction between endogenous SAP25 and SIN3A and showed that SAP25 associated with the SIN3A-HDAC complex to represses transcription.

Duong et al. (2011) analyzed protein constituents of PERIOD (PER) complexes purified from mouse tissues and identified PSF (605199). Within the complex, PSF functions to recruit SIN3A, a scaffold for assembly transcriptional inhibitory complexes; the PER complex thereby rhythmically delivers histone deacetylases to the PER1 (602260) promoter, which repress PER1 transcription. Duong et al. (2011) concluded that their findings provided a function for the PER complex and a molecular mechanism for circadian clock negative feedback.

▼ Molecular Genetics
In 6 patients from 2 unrelated families and in 3 unrelated singleton patients with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified 5 different heterozygous truncating mutations in the SIN3A gene (607776.0001-607776.0005). The mutations, which were found by exome sequencing, were predicted to result in haploinsufficiency.

▼ Animal Model
Witteveen et al. (2016) found that knockdown of Sin3a using shRNA in mice resulted in a significant reduction of cortical progenitor neurons in the proliferative zone. Loss of Sin3a also caused a change in neuronal identity, suggesting that it is required for proper differentiation, and caused aberrant corticocortical projections with abnormal callosal axon elongation and deviation compared to controls. The findings were consistent with a critical role for Sin3a in regulating the development of the mammalian cerebral cortex.

▼ History
The paper by Yao et al. (2006) regarding methylglyoxal modification of mSin3A was retracted because the panels in several figures were found to contain errors.

▼ ALLELIC VARIANTS ( 5 Selected Examples):

.0001 WITTEVEEN-KOLK SYNDROME
SIN3A, 1-BP DUP, NT803
In a 7-year-old boy (patient 5) with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified a de novo heterozygous 1-bp duplication (c.803dup, NM_001145357.1) in the SIN3A gene, resulting in a frameshift and premature termination (Leu269ThrfsTer37). The mutation, which was found by exome sequencing, was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.

.0002 WITTEVEEN-KOLK SYNDROME
SIN3A, 4-BP DEL, NT1010
In a 14-year-old girl (patient 6) with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified a de novo heterozygous 4-bp deletion (c.1010_1013del, NM_001145357.1) in the SIN3A gene, resulting in a frameshift and premature termination (Lys337SerfsTer16). The mutation, which was found by exome sequencing, was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.

.0003 WITTEVEEN-KOLK SYNDROME
SIN3A, 1-BP DEL, 1759T
In 3 members of a family (family 1, patients 7, 8, and 9) with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified a heterozygous 1-bp deletion (c.1759delT, NM_001145357.1) in the SIN3A gene, resulting in a frameshift and premature termination (Ser587ProfsTer12). The mutation, which was found by exome sequencing, was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.

.0004 WITTEVEEN-KOLK SYNDROME
SIN3A, 2-BP DEL, 2955CT
In a 9-year-old boy (patient 10) with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified a de novo heterozygous 2-bp deletion (c.2955_2956delCT, NM_001145357.1) in the SIN3A gene, resulting in a frameshift and premature termination (Glu985AspfsTer29). The mutation, which was found by exome sequencing, was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.

.0005 WITTEVEEN-KOLK SYNDROME
SIN3A, ARG1104TER
In 3 members of a family (family 2, patients 11, 12, and 13) with Witteveen-Kolk syndrome (WITKOS; 613406), Witteveen et al. (2016) identified a heterozygous c.3310C-T transition (c.3310C-T, NM_001145357.1) in the SIN3A gene, resulting in an arg1104-to-ter (R1104X) substitution. The mutation, which was found by exome sequencing, was predicted to result in nonsense-mediated mRNA decay and haploinsufficiency.

Tags: 15q24.2

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