Compound Heterozygosity for Mutations in LMNA in a Patient with a Myopathic and Lipodystrophic Mandibuloacral Dysplasia Type A Phenotype

Abstract Context: Mandibuloacral dysplasia type A (MADA; OMIM 248370) is a rare progeroid syndrome characterized by dysmorphic craniofacial and skeletal features, lipodystrophy, and metabolic complications. Most Italian patients carry the same homozygous missense mutation (p.R527H) in the C-terminal tail domain of the LMNA gene, which encodes lamin A/C, an intermediate filament component of the nuclear envelope. Objective: The objective of the study was to identify novel LMNA mutations in individuals with clinical characteristics (bird-like facies, mandibular and clavicular hypoplasia, acroosteolysis, lipodystrophy, alopecia) observed in other well-known patients. Design: The LMNA gene was sequenced. Functional properties of the mutant alleles were investigated. Patient: We report a 27-yr-old Italian woman showing a MADA-like phenotype. Features include a hypoplastic mandible, acroosteolysis, pointed nose, partial loss of sc fat, and a progeric appearance. Due to the absence of clavicular dysplasia and normal metabolic profiles, generally associated with muscle hyposthenia and generalized hypotonia, this phenotype can be considered an atypical laminopathy. Results: We identified a patient compound heterozygote for the p.R527H and p.V440M alleles. The patient’s cells showed nuclear shape abnormalities, accumulation of pre-lamin A, and irregular lamina thickness. Lamins A and C showed normal expression and localization. The electron microscopy detected heterochromatin defects with a pattern similar to those observed in other laminopathies. However, chromatin analysis showed a normal distribution pattern of the major heterochromatin proteins: heterochromatin protein-1β and histone H3 methylated at lysine 9. Conclusions: The clinical and cellular features of this patient show overlapping laminopathy phenotypes that could be due to the combination of p.R527H and p.V440M alleles.

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Atypical Progeroid Syndrome due to Heterozygous Missense LMNA Mutations

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0472 ◽

2009 ◽

Vol 94 (12) ◽

pp. 4971-4983 ◽

Cited By ~ 83

Author(s):

Abhimanyu Garg ◽

Lalitha Subramanyam ◽

Anil K. Agarwal ◽

Vinaya Simha ◽

Benjamin Levine ◽

...

Keyword(s):

Clinical Features ◽

Trichostatin A ◽

Epifluorescence Microscopy ◽

Lamin A ◽

Metabolic Complications ◽

Prelamin A ◽

Progeroid Syndrome ◽

Number Of Patients ◽

Hands And Feet ◽

Mandibuloacral Dysplasia

Context: Hutchinson-Gilford progeria syndrome (HGPS) and mandibuloacral dysplasia are well-recognized allelic autosomal dominant and recessive progeroid disorders, respectively, due to mutations in lamin A/C (LMNA) gene. Heterozygous LMNA mutations have also been reported in a small number of patients with a less well-characterized atypical progeroid syndrome (APS). Objective: The objective of the study was to investigate the underlying genetic and molecular basis of the phenotype of patients presenting with APS. Results: We report 11 patients with APS from nine families, many with novel heterozygous missense LMNA mutations, such as, P4R, E111K, D136H, E159K, and C588R. These and previously reported patients now reveal a spectrum of clinical features including progeroid manifestations such as short stature, beaked nose, premature graying, partial alopecia, high-pitched voice, skin atrophy over the hands and feet, partial and generalized lipodystrophy with metabolic complications, and skeletal anomalies such as mandibular hypoplasia and mild acroosteolysis. Skin fibroblasts from these patients when assessed for lamin A/C expression using epifluorescence microscopy revealed variable nuclear morphological abnormalities similar to those observed in patients with HGPS. However, these nuclear abnormalities in APS patients could not be rescued with 48 h treatment with farnesyl transferase inhibitors, geranylgeranyl transferase inhibitors or trichostatin-A, a histone deacetylase inhibitor. Immunoblots of cell lysates from fibroblasts did not reveal prelamin A accumulation in any of these patients. Conclusions: APS patients have a few overlapping but some distinct clinical features as compared with HGPS and mandibuloacral dysplasia. The pathogenesis of clinical manifestations in APS patients seems not to be related to accumulation of mutant farnesylated prelamin A.

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Identification of a Functional Domain Within the Essential Core of Histone H3 That Is Required for Telomeric and HM Silencing in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/163.1.447 ◽

2003 ◽

Vol 163 (1) ◽

pp. 447-452 ◽

Cited By ~ 1

Author(s):

Jeffrey S Thompson ◽

Marilyn L Snow ◽

Summer Giles ◽

Leslie E McPherson ◽

Michael Grunstein

Keyword(s):

Saccharomyces Cerevisiae ◽

Amino Acid ◽

Amino Acid Substitution ◽

Histone H3 ◽

Single Amino Acid ◽

Functional Domain ◽

Partial Loss ◽

Histone Fold ◽

Gal1 Promoter ◽

Substitution Mutations

Abstract Fourteen novel single-amino-acid substitution mutations in histone H3 that disrupt telomeric silencing in Saccharomyces cerevisiae were identified, 10 of which are clustered within the α1 helix and L1 loop of the essential histone fold. Several of these mutations cause derepression of silent mating locus HML, and an additional subset cause partial loss of basal repression at the GAL1 promoter. Our results identify a new domain within the essential core of histone H3 that is required for heterochromatin-mediated silencing.

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Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Physiological Genomics ◽

10.1152/physiolgenomics.00060.2005 ◽

2005 ◽

Vol 23 (2) ◽

pp. 150-158 ◽

Cited By ~ 80

Author(s):

Ilaria Filesi ◽

Francesca Gullotta ◽

Giovanna Lattanzi ◽

Maria Rosaria D'Apice ◽

Cristina Capanni ◽

...

Keyword(s):

Nuclear Envelope ◽

Protein A ◽

Nuclear Architecture ◽

Mendelian Inheritance ◽

Premature Aging ◽

Lamin A ◽

Lamin B ◽

Lamin B Receptor ◽

Epigenetic Events ◽

Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

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The fission yeast heterochromatin protein Rik1 is required for telomere clustering during meiosis

The Journal of Cell Biology ◽

10.1083/jcb.200312061 ◽

2004 ◽

Vol 165 (6) ◽

pp. 759-765 ◽

Cited By ~ 38

Author(s):

Creighton T. Tuzon ◽

Britta Borgstrom ◽

Dietmar Weilguny ◽

Richard Egel ◽

Julia Promisel Cooper ◽

...

Keyword(s):

Fission Yeast ◽

Mating Type ◽

Sexual Differentiation ◽

Histone H3 ◽

Heterochromatin Protein ◽

Type Locus ◽

Heterochromatin Formation ◽

Mating Type Locus ◽

Telomere Protein ◽

Chromosome Movements

Telomeres share the ability to silence nearby transcription with heterochromatin, but the requirement of heterochromatin proteins for most telomere functions is unknown. The fission yeast Rik1 protein is required for heterochromatin formation at centromeres and the mating-type locus, as it recruits the Clr4 histone methyltransferase, whose modification of histone H3 triggers binding by Swi6, a conserved protein involved in spreading of heterochromatin. Here, we demonstrate that Rik1 and Clr4, but not Swi6, are required along with the telomere protein Taz1 for crucial chromosome movements during meiosis. However, Rik1 is dispensable for the protective roles of telomeres in preventing chromosome end-fusion. Thus, a Swi6-independent heterochromatin function distinct from that at centromeres and the mating-type locus operates at telomeres during sexual differentiation.

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Tri-methylation of Histone H3 Lysine 4 Facilitates Gene Expression in Ageing Cells

10.1101/238048 ◽

2017 ◽

Cited By ~ 1

Author(s):

Cristina Cruz ◽

Monica Della Rosa ◽

Christel Krueger ◽

Qian Gao ◽

Lucy Field ◽

...

Keyword(s):

Gene Expression ◽

Budding Yeast ◽

Histone H3 ◽

Specific Factor ◽

Protein Coding ◽

Replicative Lifespan ◽

Protein Coding Genes ◽

Genome Wide ◽

Normal Expression ◽

Transcriptional Induction

AbstractTranscription of protein coding genes is accompanied by recruitment of COMPASS to promoter-proximal chromatin, which deposits di- and tri-methylation on histone H3 lysine 4 (H3K4) to form H3K4me2 and H3K4me3. Here we determine the importance of COMPASS in maintaining gene expression across lifespan in budding yeast. We find that COMPASS mutations dramatically reduce replicative lifespan and cause widespread gene expression defects. Known repressive functions of H3K4me2 are progressively lost with age, while hundreds of genes become dependent on H3K4me3 for full expression. Induction of these H3K4me3 dependent genes is also impacted in young cells lacking COMPASS components including the H3K4me3-specific factor Spp1. Remarkably, the genome-wide occurrence of H3K4me3 is progressively reduced with age despite widespread transcriptional induction, minimising the normal positive correlation between promoter H3K4me3 and gene expression. Our results provide clear evidence that H3K4me3 is required to attain normal expression levels of many genes across organismal lifespan.

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Cellular and Animal Models of Striated Muscle Laminopathies

Cells ◽

10.3390/cells8040291 ◽

2019 ◽

Vol 8 (4) ◽

pp. 291 ◽

Cited By ~ 3

Author(s):

Hannah A. Nicolas ◽

Marie-Andrée Akimenko ◽

Frédérique Tesson

Keyword(s):

Skeletal Muscle ◽

Skeletal Muscles ◽

Molecular Mechanisms ◽

Striated Muscle ◽

Nuclear Lamina ◽

The Other ◽

Lamin A ◽

Lmna Gene ◽

Future Directions ◽

Exon 10

The lamin A/C (LMNA) gene codes for nuclear intermediate filaments constitutive of the nuclear lamina. LMNA has 12 exons and alternative splicing of exon 10 results in two major isoforms—lamins A and C. Mutations found throughout the LMNA gene cause a group of diseases collectively known as laminopathies, of which the type, diversity, penetrance and severity of phenotypes can vary from one individual to the other, even between individuals carrying the same mutation. The majority of the laminopathies affect cardiac and/or skeletal muscles. The underlying molecular mechanisms contributing to such tissue-specific phenotypes caused by mutations in a ubiquitously expressed gene are not yet well elucidated. This review will explore the different phenotypes observed in established models of striated muscle laminopathies and their respective contributions to advancing our understanding of cardiac and skeletal muscle-related laminopathies. Potential future directions for developing effective treatments for patients with lamin A/C mutation-associated cardiac and/or skeletal muscle conditions will be discussed.

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