Publications by authors named "Annachiara De Sandre-Giovannoli"

55 Publications

Case Report: Identification of Novel Variants in and Genes in Two Tunisian Patients With Atypical Xeroderma Pigmentosum Phenotype.

Front Genet 2021 31;12:650639. Epub 2021 May 31.

Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, LR16IPT05, Université Tunis ElManar, Tunis, Tunisia.

Xeroderma Pigmentosum (XP) is a rare genetic disorder affecting the nucleotide excision repair system (NER). It is characterized by an extreme sensitivity to sunlight that induces cutaneous disorders such as severe sunburn, freckling and cancers. In Tunisia, six complementation groups have been already identified. However, the genetic etiology remains unknown for several patients. In this study, we investigated clinical characteristics and genetic defects in two families with atypical phenotypes originating from the central region in Tunisia. Clinical investigation revealed mild cutaneous features in two patients who develop multiple skin cancers at later ages, with no neurological disorders. Targeted gene sequencing revealed that they carried novel variants. A homozygous variation in the gene c.1762G>T, p.V588F, detected in patient XP21. As for patient XP134, he carried two homozygous mutations in the gene c.613T>C, p.C205R and c.618C>A, p.S206R. Structural modeling of the protein predicted the identified variant to mildly affect protein stability without affecting its functional domains. As for the case of DDB2 double mutant, the second variation seems to cause a mild effect on the protein structure unlike the first variation which does not seem to have an effect on it. This study contributes to further characterize the mutation spectrum of XP in Tunisian families. Targeted gene sequencing accelerated the identification of rare unexpected genetic defects for diagnostic testing and genetic counseling.
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http://dx.doi.org/10.3389/fgene.2021.650639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203331PMC
May 2021

Laminopathies' Treatments Systematic Review: A Contribution Towards a 'Treatabolome'.

J Neuromuscul Dis 2021 ;8(3):419-439

Sorbonne Université, Inserm, Center of Research in Myology, G.H. Pitié-Salpêtrière, Paris, France.

Background: Variants in the LMNA gene, encoding lamins A/C, are responsible for a growing number of diseases, all of which complying with the definition of rare diseases. LMNA-related disorders have a varied phenotypic expression with more than 15 syndromes described, belonging to five phenotypic groups: Muscular Dystrophies, Neuropathies, Cardiomyopathies, Lipodystrophies and Progeroid Syndromes. Overlapping phenotypes are also reported. Linking gene and variants with phenotypic expression, disease mechanisms, and corresponding treatments is particularly challenging in laminopathies. Treatment recommendations are limited, and very few are variant-based.

Objective: The Treatabolome initiative aims to provide a shareable dataset of existing variant-specific treatment for rare diseases within the Solve-RD EU project. As part of this project, we gathered evidence of specific treatments for laminopathies via a systematic literature review adopting the FAIR (Findable, Accessible, Interoperable, and Reusable) guidelines for scientific data production.

Methods: Treatments for LMNA-related conditions were systematically collected from MEDLINE and Embase bibliographic databases and clinical trial registries (Cochrane Central Registry of Controlled Trials, clinicaltrial.gov and EudraCT). Two investigators extracted and analyzed the literature data independently. The included papers were assessed using the Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

Results: From the 4783 selected articles by a systematic approach, we identified 78 papers for our final analysis that corresponded to the profile of data defined in the inclusion and exclusion criteria. These papers include 2 guidelines/consensus papers, 4 meta-analyses, 14 single-arm trials, 15 case series, 13 cohort studies, 21 case reports, 8 expert reviews and 1 expert opinion. The treatments were summarized electronically according to significant phenome-genome associations. The specificity of treatments according to the different laminopathic phenotypical presentations is variable.

Conclusions: We have extracted Treatabolome-worthy treatment recommendations for patients with different forms of laminopathies based on significant phenome-genome parings. This dataset will be available on the Treatabolome website and, through interoperability, on genetic diagnosis and treatment support tools like the RD-Connect's Genome Phenome Analysis Platform.
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http://dx.doi.org/10.3233/JND-200596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203247PMC
January 2021

Gene Mutations in North African Fanconi Anemia Patients.

Front Genet 2021 19;12:610050. Epub 2021 Feb 19.

Department of Histology and Cytogenetics, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.

Populations in North Africa (NA) are characterized by a high rate of consanguinity. Consequently, the proportion of founder mutations might be higher than expected and could be a major cause for the high prevalence of recessive genetic disorders like Fanconi anemia (FA). We report clinical, cytogenetic, and molecular characterization of in 29 North African FA patients from Tunisia, Libya, and Algeria. Cytogenetic tests revealed high rates of spontaneous chromosome breakages for all patients except two of them. molecular analysis was performed using three different molecular approaches which allowed us to identify causal mutations as homozygous or compound heterozygous forms. It included a nonsense mutation (c.2749C > T; p.Arg917Ter), one reported missense mutation (c.1304G > A; p.Arg435His), a novel missense variant (c.1258G > A; p.Asp409Glu), and the most common reported mutation (c.3788_3790delTCT; p.Phe1263del). Furthermore, three founder mutations were identified in 86.7% of the 22 Tunisian patients: (1) a deletion of exon 15, in 36.4% patients (8/22); (2), a deletion of exons 4 and 5 in 23% (5/22) and (3) an intronic mutation c.2222 + 166G > A, in 27.3% (6/22). Despite the relatively small number of patients studied, our results depict the mutational landscape of FA among NA populations and it should be taken into consideration for appropriate genetic counseling.
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http://dx.doi.org/10.3389/fgene.2021.610050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933650PMC
February 2021

Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype.

Eur J Hum Genet 2021 Apr 12;29(4):625-636. Epub 2021 Jan 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Witteveen-Kolk syndrome (OMIM 613406) is a recently defined neurodevelopmental syndrome caused by heterozygous loss-of-function variants in SIN3A. We define the clinical and neurodevelopmental phenotypes related to SIN3A-haploinsufficiency in 28 unreported patients. Patients with SIN3A variants adversely affecting protein function have mild intellectual disability, growth and feeding difficulties. Involvement of a multidisciplinary team including a geneticist, paediatrician and neurologist should be considered in managing these patients. Patients described here were identified through a combination of clinical evaluation and gene matching strategies (GeneMatcher and Decipher). All patients consented to participate in this study. Mean age of this cohort was 8.2 years (17 males, 11 females). Out of 16 patients ≥ 8 years old assessed, eight (50%) had mild intellectual disability (ID), four had moderate ID (22%), and one had severe ID (6%). Four (25%) did not have any cognitive impairment. Other neurological symptoms such as seizures (4/28) and hypotonia (12/28) were common. Behaviour problems were reported in a minority. In patients ≥2 years, three were diagnosed with Autism Spectrum Disorder (ASD) and four with Attention Deficit Hyperactivity Disorder (ADHD). We report 27 novel variants and one previously reported variant. 24 were truncating variants; three were missense variants and one large in-frame gain including exons 10-12.
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http://dx.doi.org/10.1038/s41431-020-00769-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115148PMC
April 2021

Loss of MTX2 causes mandibuloacral dysplasia and links mitochondrial dysfunction to altered nuclear morphology.

Nat Commun 2020 09 11;11(1):4589. Epub 2020 Sep 11.

Aix Marseille Univ, INSERM, MMG, U1251, Marseille, France.

Mandibuloacral dysplasia syndromes are mainly due to recessive LMNA or ZMPSTE24 mutations, with cardinal nuclear morphological abnormalities and dysfunction. We report five homozygous null mutations in MTX2, encoding Metaxin-2 (MTX2), an outer mitochondrial membrane protein, in patients presenting with a severe laminopathy-like mandibuloacral dysplasia characterized by growth retardation, bone resorption, arterial calcification, renal glomerulosclerosis and severe hypertension. Loss of MTX2 in patients' primary fibroblasts leads to loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment. Furthermore, patients' fibroblasts are resistant to induced apoptosis, leading to increased cell senescence and mitophagy and reduced proliferation. Interestingly, secondary nuclear morphological defects are observed in both MTX2-mutant fibroblasts and mtx-2-depleted C. elegans. We thus report the identification of a severe premature aging syndrome revealing an unsuspected link between mitochondrial composition and function and nuclear morphology, establishing a pathophysiological link with premature aging laminopathies and likely explaining common clinical features.
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http://dx.doi.org/10.1038/s41467-020-18146-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486921PMC
September 2020

Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13.

Nat Commun 2020 08 17;11(1):4110. Epub 2020 Aug 17.

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaMmp13 mice or LmnaMmp13 mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.
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http://dx.doi.org/10.1038/s41467-020-17901-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431909PMC
August 2020

Expanding the Spectrum of Neurological Manifestations in Cutis Laxa, Autosomal Recessive, Type IIIA.

Neuropediatrics 2020 08 6;51(4):245-250. Epub 2020 Mar 6.

Service de Neurologie Pédiatrique, CHU de Bordeaux, Bordeaux, France.

Cutis laxa is a heterogeneous group of diseases, characterized by abundant and wrinkled skin and a variable degree of intellectual disability. Cutis laxa, autosomal recessive, type IIIA and autosomal dominant 3 syndromes are caused by autosomal recessive or de novo pathogenic variants in . Autosomal recessive variants are known to lead to the most severe neurological phenotype, and very few patients have been described.We describe a 13-month-old patient with cutis laxa, autosomal recessive, type IIIA, with an extremely severe phenotype, including novel neurological findings. This description enlarges the neurological spectrum associated to cutis laxa, autosomal recessive, type IIIA, and provides an additional description of this syndrome.
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http://dx.doi.org/10.1055/s-0040-1701671DOI Listing
August 2020

Outcomes of 4 years of molecular genetic diagnosis on a panel of genes involved in premature aging syndromes, including laminopathies and related disorders.

Orphanet J Rare Dis 2019 12 11;14(1):288. Epub 2019 Dec 11.

Department of Medical Genetics, Assistance Publique Hopitaux de Marseille, Marseille, France.

Background: Segmental progeroid syndromes are a heterogeneous group of rare and often severe genetic disorders that have been studied since the twentieth century. These progeroid syndromes are defined as segmental because only some of the features observed during natural aging are accelerated.

Methods: Since 2015, the Molecular Genetics Laboratory in Marseille La Timone Hospital proposes molecular diagnosis of premature aging syndromes including laminopathies and related disorders upon NGS sequencing of a panel of 82 genes involved in these syndromes. We analyzed the results obtained in 4 years on 66 patients issued from France and abroad.

Results: Globally, pathogenic or likely pathogenic variants (ACMG class 5 or 4) were identified in about 1/4 of the cases; among these, 9 pathogenic variants were novel. On the other hand, the diagnostic yield of our panel was over 60% when the patients were addressed upon a nosologically specific clinical suspicion, excepted for connective tissue disorders, for which clinical diagnosis may be more challenging. Prenatal testing was proposed to 3 families. We additionally detected 16 variants of uncertain significance and reclassified 3 of them as benign upon segregation analysis in first degree relatives.

Conclusions: High throughput sequencing using the Laminopathies/ Premature Aging disorders panel allowed molecular diagnosis of rare disorders associated with premature aging features and genetic counseling for families, representing an interesting first-level analysis before whole genome sequencing may be proposed, as a future second step, by the National high throughput sequencing platforms ("Medicine France Genomics 2025" Plan), in families without molecular diagnosis.
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http://dx.doi.org/10.1186/s13023-019-1189-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6907233PMC
December 2019

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

Circulation 2019 07 3;140(4):293-302. Epub 2019 Jun 3.

APHM, Centre de référence des maladies neuromusculaires PACA-Réunion-Rhône Alpes, Hôpital Timone; Aix Marseille Université, Inserm UMR_S 910, GMGF, France (E.S.).

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation.

Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range].

Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach.

Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.039410DOI Listing
July 2019

Identification of a ERCC5 c.2333T>C (L778P) Variant in Two Tunisian Siblings With Mild Xeroderma Pigmentosum Phenotype.

Front Genet 2019 14;10:111. Epub 2019 Feb 14.

Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, Université de Tunis El Manar, Tunis, Tunisia.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder due to a defect in the nucleotide excision repair (NER) DNA repair pathway, characterized by severe sunburn development of freckles, premature skin aging, and susceptibility to develop cancers at an average age of eight. XP is an example of accelerated photo-aging. It is a genetically and clinically heterogeneous disease. Eight complementation groups have been described worldwide. In Tunisia, five groups have been already identified. In this work, we investigated the genetic etiology in a family with an atypically mild XP phenotype. Two Tunisian siblings born from first-degree consanguineous parents underwent clinical examination in the dermatology department of the Charles Nicolle Hospital on the basis of acute sunburn reaction and mild neurological disorders. Blood samples were collected from two affected siblings after written informed consent. As all mutations reported in Tunisia have been excluded using Sanger sequencing, we carried out mutational analysis through a targeted panel of gene sequencing using the Agilent HaloPlex target enrichment system. Our clinical study shows, in both patients, the presence of achromic macula in sun exposed area with dermatological feature suggestive of Xeroderma pigmentosum disease. No developmental and neurological disorders were observed except mild intellectual disability. Genetic investigation shows that both patients were carriers of an homozygous T to C transition at the nucleotide position c.2333, causing the leucine to proline amino acid change at the position 778 (p.Leu778Pro) of the gene, and resulting in an XP-G phenotype. The same variation was previously reported at the heterozygous state in a patient cell line in Europe, for which no clinical data were available and was suggested to confer an XP/CS phenotype based on functional tests. This study contributes to further characterization of the mutation spectrum of XP in consanguineous Tunisian families and is potentially helpful for early diagnosis. It also indicates that the genotype-phenotype correlation is not always coherent for patients with mild clinical features. These data therefore suggest that targeted NGS is a highly informative diagnostic strategy, which can be used for XP molecular etiology determination.
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http://dx.doi.org/10.3389/fgene.2019.00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383105PMC
February 2019

Lamin A/C gene (LMNA) mutation associated with laminopathy: A rare cause of idiopathic acro-osteolysis.

Joint Bone Spine 2019 07 6;86(4):525-527. Epub 2018 Dec 6.

CHU de Caen, department of rheumatology, avenue de la Côte de Nacre, Caen, 14000, France; Université Caen Normandie, medical School, Caen, 14000, France.

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http://dx.doi.org/10.1016/j.jbspin.2018.11.008DOI Listing
July 2019

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome.

BMC Pediatr 2018 08 29;18(1):286. Epub 2018 Aug 29.

Aix Marseille University, INSERM, GMGF, Marseille, France.

Background: Noonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of several genes belonging to the RAS Mitogen Activated Protein Kinase (MAPK) signaling pathway. Incontinentia Pigmenti (IP) is an X-linked, dominantly inherited multisystem disorder.

Case Presentation: This study is the first report of the coexistence of Noonan (NS) and Incontinentia Pigmenti (IP) syndromes in the same patient. We report on the clinical phenotype and molecular characterization of this patient. The patient was examined by a pluridisciplinary staff of clinicians and geneticist. The clinical diagnosis of NS and IP was confirmed by molecular investigations. The newborn girl came to our clinics due to flagrant dysmorphia and dermatological manifestations. The clinical observations led to characterize the Incontinentia Pigmenti traits and a suspicion of a Noonan syndrome association. Molecular diagnosis was performed by Haloplex resequencing of 29 genes associated with RASopathies and confirmed the NS diagnosis. The common recurrent intragenic deletion mutation in IKBKG gene causing the IP was detected with an improved PCR protocol.

Conclusion: This is the first report in the literature of comorbidity of NS and IP, two rare multisystem syndromes.
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http://dx.doi.org/10.1186/s12887-018-1259-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116546PMC
August 2018

Pathological modelling of pigmentation disorders associated with Hutchinson-Gilford Progeria Syndrome (HGPS) revealed an impaired melanogenesis pathway in iPS-derived melanocytes.

Sci Rep 2018 06 14;8(1):9112. Epub 2018 Jun 14.

CECS, I-Stem, Corbeil-Essonnes, 91100, France.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that leads to premature aging. In this study, we used induced pluripotent stem cells to investigate the hypopigmentation phenotypes observed in patients with progeria. Accordingly, two iPS cell lines were derived from cells from HGPS patients and differentiated into melanocytes. Measurements of melanin content revealed a lower synthesis of melanin in HGPS melanocytes as compared to non-pathologic cells. Analysis of the melanosome maturation process by electron microscopy revealed a lower percentage of mature, fully pigmented melanosomes. Finally, a functional rescue experiment revealed the direct role of progerin in the regulation of melanogenesis. Overall, these results report a new dysregulated pathway in HGPS and open up novel perspectives in the study of pigmentation phenotypes that are associated with normal and pathological aging.
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http://dx.doi.org/10.1038/s41598-018-27165-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002548PMC
June 2018

Substrate Topography Modulates Cell Aging on a Progeria Cell Model.

ACS Biomater Sci Eng 2018 May 26;4(5):1498-1504. Epub 2018 Apr 26.

Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, Faculty of Medicine, Polo I first Floor, 3004-504 Coimbra, Portugal.

Aging is characterized by a progressive accumulation of cellular damage, which leads to impaired function. Little is known whether substrates can influence cell aging. This is of utmost importance in the development of medical devices that are in contact with human tissue for long periods of time. To address this question, we have used an accelerated aging cell model derived from Hutchinson-Gilford Progeria Syndrome (HGPS) induced pluripotent stem cells (iPSCs). Our results show that HGPS-iPSC smooth muscle cells (SMCs) have an increased aging profile in substrates with specific micropatterns than in flat ones. This is characterized by an up-regulation in the expression of progerin, β-galactosidase, annexin 3 and 5, and caspase 9. Signs of cell aging are also observed in SMCs without HGPS cultured in substrates with specific microtopographies. It is further showed that specific micropatterned substrates induce cell aging by triggering a DNA damage program likely by the disruption between cyto- and nucleoskeleton.
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http://dx.doi.org/10.1021/acsbiomaterials.8b00224DOI Listing
May 2018

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies.

Aging Cell 2018 08 25;17(4):e12766. Epub 2018 Apr 25.

Aix Marseille Univ, INSERM, MMG, Marseille, France.

Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue-specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR-9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation.
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http://dx.doi.org/10.1111/acel.12766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052405PMC
August 2018

An overview of treatment strategies for Hutchinson-Gilford Progeria syndrome.

Nucleus 2018 01;9(1):246-257

a Aix Marseille Univ, INSERM, MMG - U1251 , Marseille , France.

Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS.
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http://dx.doi.org/10.1080/19491034.2018.1460045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973194PMC
January 2018

Low lamin A expression in lung adenocarcinoma cells from pleural effusions is a pejorative factor associated with high number of metastatic sites and poor Performance status.

PLoS One 2017 14;12(8):e0183136. Epub 2017 Aug 14.

Aix Marseille Univ, INSERM, GMGF, Marseille, France.

The type V intermediate filament lamins are the principal components of the nuclear matrix, including the nuclear lamina. Lamins are divided into A-type and B-type, which are encoded by three genes, LMNA, LMNB1, and LMNB2. The alternative splicing of LMNA produces two major A-type lamins, lamin A and lamin C. Previous studies have suggested that lamins are involved in cancer development and progression. A-type lamins have been proposed as biomarkers for cancer diagnosis, prognosis, and/or follow-up. The aim of the present study was to investigate lamins in cancer cells from metastatic pleural effusions using immunofluorescence, western blotting, and flow cytometry. In a sub-group of lung adenocarcinomas, we found reduced expression of lamin A but not of lamin C. The reduction in lamin A expression was correlated with the loss of epithelial membrane antigen (EMA)/MUC-1, an epithelial marker that is involved in the epithelial to mesenchymal transition (EMT). Finally, the lamin A expression was inversely correlated with the number of metastatic sites and the WHO Performance status, and association of pleural, bone and lung metastatic localizations was more frequent when lamin A expression was reduced. In conclusion, low lamin A but not lamin C expression in pleural metastatic cells could represent a major actor in the development of metastasis, associated with EMT and could account for a pejorative factor correlated with a poor Performance status.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183136PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555706PMC
October 2017

Metformin decreases progerin expression and alleviates pathological defects of Hutchinson-Gilford progeria syndrome cells.

NPJ Aging Mech Dis 2016 10;2:16026. Epub 2016 Nov 10.

INSERM U861, I-STEM, AFM, Institute for Stem cell Therapy and Exploration of Monogenic Diseases, Corbeil Essonnes, France.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder that causes systemic accelerated aging in children. This syndrome is due to a mutation in the gene that leads to the production of a truncated and toxic form of lamin A called progerin. Because the balance between the A-type lamins is controlled by the RNA-binding protein SRSF1, we have hypothesized that its inhibition may have therapeutic effects for HGPS. For this purpose, we evaluated the antidiabetic drug metformin and demonstrated that 48 h treatment with 5 mmol/l metformin decreases SRSF1 and progerin expression in mesenchymal stem cells derived from HGPS induced pluripotent stem cells (HGPS MSCs). The effect of metformin on progerin was then confirmed in several models of HGPS, i.e., human primary HGPS fibroblasts, mouse fibroblasts and healthy MSCs previously treated with a PMO (phosphorodiamidate morpholino oligonucleotide) that induces progerin. This was accompanied by an improvement in two phenotypes associated with the disease: nuclear shape abnormalities and premature osteoblastic differentiation of HGPS MSCs. Overall, these results suggest a novel approach towards therapeutics for HGPS that can be added to the currently assayed treatments that target other molecular defects associated with the disease.
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http://dx.doi.org/10.1038/npjamd.2016.26DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515002PMC
November 2016

MG132-induced progerin clearance is mediated by autophagy activation and splicing regulation.

EMBO Mol Med 2017 09;9(9):1294-1313

Aix Marseille Univ, INSERM, GMGF (Génétique Médicale et Génomique Fonctionnelle), Marseille, France

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a point mutation in encoding A-type lamins. Progerin, a truncated and toxic prelamin A issued from aberrant splicing, accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. We show that progerin is sequestered into abnormally shaped promyelocytic nuclear bodies, identified as novel biomarkers in late passage HGPS cell lines. We found that the proteasome inhibitor MG132 induces progerin degradation through macroautophagy and strongly reduces progerin production through downregulation of SRSF-1 and SRSF-5 accumulation, controlling prelamin A mRNA aberrant splicing. MG132 treatment improves cellular HGPS phenotypes. MG132 injection in skeletal muscle of mice locally reduces SRSF-1 expression and progerin levels. Altogether, we demonstrate progerin reduction based on MG132 dual action and shed light on a promising class of molecules toward a potential therapy for children with HGPS.
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http://dx.doi.org/10.15252/emmm.201607315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582415PMC
September 2017

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

Metabolism 2017 06 28;71:213-225. Epub 2017 Mar 28.

Aix Marseille Univ, INSERM, GMGF, Marseille, France; Department of Medical Genetics, Molecular genetics Laboratory, La Timone Children's Hospital, 264 Rue Saint Pierre, 13005, Marseille, France. Electronic address:

Background: Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition.

Patients And Methods: We describe a male and a female patient with MDPL respectively affected with mild and severe phenotypes. Both of them showed mandibular hypoplasia, a beaked nose with bird-like facies, prominent eyes, a small mouth, growth retardation, muscle and skin atrophy, but the female patient showed such a severe and early phenotype that a first working diagnosis of Hutchinson-Gilford Progeria was made. The exploration was performed by direct sequencing of POLD1 gene exon 15 in the male patient with a classical MDPL phenotype and by whole exome sequencing in the female patient and her unaffected parents.

Results: Exome sequencing identified in the latter patient a de novo heterozygous undescribed mutation in the POLD1 gene (NM_002691.3: c.3209T>A), predicted to cause the missense change p.Ile1070Asn in the ZnF2 (Zinc Finger 2) domain of the protein. This mutation was not reported in the 1000 Genome Project, dbSNP and Exome sequencing databases. Furthermore, the Isoleucine1070 residue of POLD1 is highly conserved among various species, suggesting that this substitution may cause a major impairment of POLD1 activity. For the second patient, affected with a typical MDPL phenotype, direct sequencing of POLD1 exon 15 revealed the recurrent in-frame deletion (c.1812_1814del, p.S605del).

Conclusion: Our work highlights that mutations in different POLD1 domains can lead to phenotypic variability, ranging from dominantly inherited cancer predisposition syndromes, to mild MDPL phenotypes without lifespan reduction, to very severe MDPL syndromes with major premature aging features. These results also suggest that POLD1 gene testing should be considered in patients presenting with severe progeroid features.
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http://dx.doi.org/10.1016/j.metabol.2017.03.011DOI Listing
June 2017

A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells.

Sci Rep 2016 10 14;6:34798. Epub 2016 Oct 14.

CECS, I-STEM, AFM, Institute for Stem cell Therapy and Exploration of Monogenic diseases, 2 rue Henri Desbruères, 91100 Corbeil-Essonnes, France.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation. Results revealed seven compounds that normalized the osteogenic differentiation process and, among these, all-trans retinoic acid and 13-cis-retinoic acid, that also decreased progerin expression. This study highlights the potential of high-throughput drug screening using HGPS iPS-derived cells, in order to find therapeutic compounds for HGPS and, potentially, for other aging-related disorders.
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http://dx.doi.org/10.1038/srep34798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064407PMC
October 2016

Antisense-Based Progerin Downregulation in HGPS-Like Patients' Cells.

Cells 2016 Jul 11;5(3). Epub 2016 Jul 11.

Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, France.

Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A Δ50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named "HGPS-like" patients. They also produce Progerin and/or other truncated Prelamin A isoforms (Δ35 and Δ90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A Δ35, Prelamin A Δ90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5040973PMC
http://dx.doi.org/10.3390/cells5030031DOI Listing
July 2016

Novel mutations cause an aggressive atypical neonatal progeria without progerin accumulation.

J Med Genet 2016 Nov 22;53(11):776-785. Epub 2016 Jun 22.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.

Background: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally caused by mutations in leading to accumulation of the toxic protein progerin and consequently, to nuclear envelope alterations. In this work, we describe a novel phenotypic feature of the progeria spectrum affecting three unrelated newborns and identify its genetic cause.

Methods And Results: Patients reported herein present an extremely homogeneous phenotype that somewhat recapitulates those of patients with HGPS and mandibuloacral dysplasia. However, pathological signs appear earlier, are more aggressive and present distinctive features including episodes of severe upper airway obstruction. Exome and Sanger sequencing allowed the identification of heterozygous de novo c.163G>A, p.E55K and c.164A>G, p.E55G mutations in as the alterations responsible for this disorder. Functional analyses demonstrated that fibroblasts from these patients suffer important dysfunctions in nuclear lamina, which generate profound nuclear envelope abnormalities but without progerin accumulation. These nuclear alterations found in patients' dermal fibroblasts were also induced by ectopic expression of the corresponding site-specific mutants in control human fibroblasts.

Conclusions: Our results demonstrate the causal role of p.E55K and p.E55G lamin A mutations in a disorder which manifests novel phenotypic features of the progeria spectrum characterised by neonatal presentation and aggressive clinical evolution, despite being caused by lamin A/C missense mutations with effective prelamin A processing.
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http://dx.doi.org/10.1136/jmedgenet-2015-103695DOI Listing
November 2016

A novel overlapping phenotype characterized by lipodystrophy, mandibular dysplasia, and dilated cardiomyopathy associated with a new mutation in the LMNA gene.

Int J Cardiol 2016 Apr 16;209:317-8. Epub 2016 Feb 16.

Department of Medical Genetics, La Timone Hospital, Aix Marseille Université, INSERM, GMGF UMR S 910, 13385 Marseille, France.

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http://dx.doi.org/10.1016/j.ijcard.2016.02.113DOI Listing
April 2016

[First Italo-French meeting on laminopathies and other pathologies related to the nuclear envelope].

Med Sci (Paris) 2015 Nov 6;31 Spec No 3:39-40. Epub 2015 Nov 6.

Sorbonne Universités, UPMC Université Paris 06, Inserm UMRS974, CNRS FRE3617, Centre de Recherche en Myologie, Institut de Myologie, Paris, France.

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http://dx.doi.org/10.1051/medsci/201531s311DOI Listing
November 2015

Truncated prelamin A expression in HGPS-like patients: a transcriptional study.

Eur J Hum Genet 2015 Aug 4;23(8):1051-61. Epub 2015 Feb 4.

1] Aix Marseille Université, INSERM, GMGF UMR_S 910, Marseille, France [2] Département de Génétique Médicale et de Biologie Cellulaire, AP-HM, Hôpital d'Enfants de la Timone, Marseille, France.

Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11.
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http://dx.doi.org/10.1038/ejhg.2014.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795109PMC
August 2015

Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome.

BMC Med Genet 2014 May 2;15:51. Epub 2014 May 2.

Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, 33006 Oviedo, Spain.

Background: SHORT syndrome is a rare autosomal dominant condition whose name is the acronym of short stature, hyperextensibility of joints, ocular depression, Rieger anomaly and teething delay (MIM 269880). Additionally, the patients usually present a low birth weight and height, lipodystrophy, delayed bone age, hernias, low body mass index and a progeroid appearance.

Case Presentation: In this study, we used whole-exome sequencing approaches in two patients with clinical features of SHORT syndrome. We report the finding of a novel mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8), as well as a recurrent mutation c.1945C > T (p.Arg649Trp) in this gene.

Conclusions: We found a novel frameshift mutation in PIK3R1 (c.1929_1933delTGGCA; p.Asp643Aspfs*8) which consists of a deletion right before the site of substrate recognition. As a consequence, the protein lacks the position that interacts with the phosphotyrosine residue of the substrate, resulting in the development of SHORT syndrome.
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http://dx.doi.org/10.1186/1471-2350-15-51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022398PMC
May 2014

A new lamin a mutation associated with acrogeria syndrome.

J Invest Dermatol 2014 Aug 1;134(8):2274-2277. Epub 2014 Apr 1.

Aix Marseille Université, GMGF, INSERM, UMR_S 910, Marseille, France. Electronic address:

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http://dx.doi.org/10.1038/jid.2014.158DOI Listing
August 2014

WITHDRAWN: Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective.

Semin Cell Dev Biol 2014 Mar 28. Epub 2014 Mar 28.

Aix-Marseille Université, UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France(1); INSERM, UMR_S 910, Génétique Médicale et Génomique Fonctionnelle, Faculté de Médecine, 27 Bd Jean Moulin, 13385 Marseille Cedex 5, France(1); AP-HM, Département de Génétique Médicale, Hôpital d'enfants Timone, 264 Rue Saint Pierre, 13385 Marseille Cedex 5, France(3). Electronic address:

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.semcdb.2014.03.022. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
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http://dx.doi.org/10.1016/j.semcdb.2014.03.022DOI Listing
March 2014
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