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1.
Genet Med ; 23(2): 384-395, 2021 02.
Article in English | MEDLINE | ID: mdl-33173220

ABSTRACT

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.


Subject(s)
Autism Spectrum Disorder , Intellectual Disability , Autism Spectrum Disorder/genetics , Chromosomal Proteins, Non-Histone , DNA-Binding Proteins , Female , Genes, X-Linked , Genotype , Humans , Intellectual Disability/genetics , Male , Phenotype , Exome Sequencing
2.
Mol Biol Cell ; 16(6): 2605-13, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15788561

ABSTRACT

The general transcriptional repressor Tup1 is responsible for the regulation of a large, diverse set of genes in Saccharomyces cerevisiae, and functional homologues of Tup1 have been identified in many metazoans. The crystal structure for the C-terminal portion of Tup1 has been solved and, when sequences of Tup1 homologues from fungi and metazoans were compared, a highly conserved surface was revealed. In this article, we analyze five point mutations that lie on this conserved surface. A statistical analysis of expression microarrays demonstrates that the mutant alleles are deficient in the repression of different subsets of Tup1-regulated genes. We were able to rank the mutant alleles of TUP1 based on the severity of their repression defects measured both by the number of genes derepressed and by the magnitude of that derepression. For one particular class of genes, the mutations on the conserved surface disrupted recruitment of Tup1 to the repressed promoters. However, for the majority of the genes derepressed by the Tup1 point mutants, recruitment of Tup1 to the regulated promoters is largely unaffected. These mutations affect the mechanism of repression subsequent to recruitment of the complex and likely represent a disruption of a mechanism that is conserved in fungi and metazoans. This work demonstrates that the evolutionarily conserved surface of Tup1 interacts with two separate types of proteins-sequence-specific DNA-binding proteins responsible for recruiting Tup1 to promoters as well as components that are likely to function in a conserved repression mechanism.


Subject(s)
DNA-Binding Proteins/metabolism , Fungal Proteins/metabolism , Genome, Fungal , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Alanine/metabolism , Alleles , Amino Acid Substitution , Chromatin Immunoprecipitation , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Fungal Proteins/chemistry , Fungal Proteins/genetics , Gene Expression Regulation, Fungal , Genes, Fungal , Models, Biological , Models, Molecular , Nuclear Proteins/chemistry , Nuclear Proteins/genetics , Oligonucleotide Array Sequence Analysis , Point Mutation , Promoter Regions, Genetic , Protein Structure, Tertiary , Repressor Proteins/chemistry , Repressor Proteins/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/genetics , Transcription, Genetic , beta-Galactosidase/analysis , beta-Galactosidase/metabolism
3.
Mol Biol Cell ; 15(9): 4191-202, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15240822

ABSTRACT

The Tup1-Ssn6 complex has been well characterized as a Saccharomyces cerevisiae general transcriptional repressor with functionally conserved homologues in metazoans. These homologues are essential for cell differentiation and many other developmental processes. The mechanism of repression of all of these proteins remains poorly understood. Srb10 (a cyclin-dependent kinase associated with the Mediator complex) and Hda1 (a class I histone deacetylase) have each been implicated in Tup1-mediated repression. We present a statistically based genome-wide analysis that reveals that Hda1 partially represses roughly 30% of Tup1-repressed genes, whereas Srb10 kinase activity contributes to the repression of approximately 15% of Tup1-repressed genes. These effects only partially overlap, suggesting that different Tup1-repression mechanisms predominate at different promoters. We also demonstrate a distinction between histone deacetylation and transcriptional repression. In an HDA1 deletion, many Tup1-repressed genes are hyperacetylated at lysine 18 of histone H3, yet are not derepressed, indicating deacetylation alone is not sufficient to repress most Tup1-controlled genes. In a strain lacking both Srb10 and Hda1 functions, more than half of the Tup1-repressed genes are still repressed, suggesting that Tup1-mediated repression occurs by multiple, partially overlapping mechanisms, at least one of which is unknown.


Subject(s)
Cyclin-Dependent Kinases/metabolism , Fungal Proteins/metabolism , Histone Deacetylases/metabolism , Nuclear Proteins/metabolism , Repressor Proteins/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Acetylation , Cyclin-Dependent Kinase 8 , Cyclin-Dependent Kinases/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Fungal Proteins/genetics , Gene Deletion , Gene Expression Profiling , Genes, Fungal , Histone Deacetylases/genetics , Histones/genetics , Histones/metabolism , Models, Biological , Nuclear Proteins/genetics , Promoter Regions, Genetic , Repressor Proteins/genetics , Saccharomyces cerevisiae Proteins/genetics , Transcription, Genetic
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