On aging, reproduction and cell division : what cells teach us about genetic disorders

Unlike bacterial cells, our cells and those of all eukaryotes have a nucleus, an organelle that contains our genetic material, encoded by our DNA. The nuclear envelope not only protects the DNA that it surrounds, but is also important to regulate chromosome dynamics and gene expression, as well as to control the transport of different molecules to and from the cytoplasm. Given the importance of its functions, it is not surprising that defects in the proteins of the nuclear envelope can have dramatic consequences in a cell. These defects are responsible for a familiy of disorders called laminopathies with a wide spectrum of pathological manifestations.
In 2003, researchers and clinicians from the AgiPreC departement discovered that the LMNA gene, which encodes two nuclear proteins called Lamins A and C, was responsible for Progeria (or Hutchinson-Gilford progeria syndrome, HGPS), the most commonly known but also the rarest of all laminopathies. Since then, the scientists have identified a number of related disorders, all of which are due to defects in nuclear proteins (premature aging disorders and lipodystrophies). They now also focus on understanding how these same proteins could play a role in completely different disorders, including defects in spermatogenesis and cancer. The department aims at improving the diagnostics of these diseases as well as uncovering the mechanistic defects that are responsible for their onset and developing therapeutic strategies to treat affected patients.

1999 :  by discovering the gene responsible for the dominant form of the Emery-Dreifuss muscular dystrophy, Gisèle Bonne and colleagues describe the founding member of what will later become  a new clinical entity : laminopathies. Only three years later, Nicolas Lévy and his colleagues find that mutations in the very same LMNA gene are responsible for Charcot-Marie-Tooth disease, an inherited neurological disorder characterised by the loss of touch sensation as well as the ability to walk. The team further solve a century-old puzzle by demonstrating in 2003 the implication of the LMNA gene in Progeria, a rare uncurable disorder that results in premature and accelerated aging. Children suffering from this systemic disease present with a wide range of symptoms (lipodystrophy, alopecia, osteoarthritis, osteoporosis, vascular disorders while the cognitive functions remain intact) and die early on (at an average of 13 years), usually from a heart attack or a stroke.

« Progeria was known since the end of the 19th century and yet by the early 21st century, scientist had no clue of the gene that caused this disease», reminds Nicolas Lévy. « Shortly after finding mutations in the LMNA gene among patients suffering from Charcot-Marie-Tooth disease, we noticed that certain patients who carried other mutations in the gene presented with signs of accelerated aging. That’s when we found defects in this gene among Progeria patients ».

Progerin, a toxic variant of lamin A

Located on chromosome 1, the LMNA gene encodes two proteins belonging to the family of intermediate filaments : lamins A and C (every gene can encode several proteins, or isoforms, that are produced by a mechanism called alternative splicing). Once synthesized, lamin A undergoes a series of maturation steps before becoming fully functional. These include the attachement of a farnesyl group to a specific region of the protein (a step called prenylation), after which it enters the nucleus and the farnesyl group is cleaved off. The proteins then combine with one another and with lamins C and B (the latter being encoded by a different gene) to integrate the nuclear matrix and cover the inner surface of the nuclear envelope, thereby forming the nuclear lamina. This structure ensures the dynamic movement of chromosomes and controls the transport of molecules accross the nuclear pores.

In progeria cells, the mutated LMNA gene produces a truncated version of lamin A that bears a deletion of 50 amino acids and is called progerin. The mutant protein remains attached to its farnesyl group, which produces aberrant interactions with other lamins  as well as other proteins of the nuclear matrix and lamina. These structures become disorganised causing a series of dysfunctions in the cell. « The progressive accumulation of progerin has several toxic effects, including abnormal shaping of the nucleus and modifications in chromatin structure. As a result, several nuclear functions are disturbed (DNA replication and repair, transcription, RNA splicing, protein transport accross the nuclear pores…) leading to premature aging and cell death » explains Nicolas Lévy. « Given that progerin is ubiquitous,  these defects concern almost every differentiated cell of the body, which explains the diversity and severity of clinical signs found in progeria patients ».

The laboratory since works towards further understanding laminopathies as well as other diseases that result from defects in proteins of the nuclear envelope. To date, over 270 mutations in the LMNA gene have been identified, and the number of disorders linked to these mutations is constantly growing. It now includes several porgeroïd syndromes, lipodystrophies, Limb-girdle muscular dystrophy type 1B, dilated cardiomyopathy with cardiac conduction disturbances, in addition to the previously known Emery-Dreifuss muscular dystrophy, Charcot-Marie-Tooth disease and Progeria.

The team’s efforts have also opened the door to potential therapeutic solutions for the treatment of Progeria. Two strategies are currently being developed by the team: the first aims to reduce the toxicity of progerin, while the second aims to limit the protein overflow.

Reducing the toxicity of progerin

The scientists from the AgiPreC department used two existing farnesyl transferase inhibitors to block the prenylation of progerin: Prevastatine (a statin used to lower cholesterol and triglycerides in the blood) and Zoledronate (a drug used to treat osteoporosis as well as pain from bone metastases). They first showed that the combination of the two had beneficial effects in vitro, before demonstrating in 2008 the potential of the bitherapy on the first mouse model of Progeria (a model in which a toxic prenylated prelamin A accumulates in the cells).
« In collaboration with the laboratory of Carlos Lopez−Otin at University of Oviedo, we demonstrated that a treatment based on the association of the two farnesyl transferase inhibitors significantly improved bone density and life expectancy of affected mice (173 days in average) » explains Annachiara De Sandre-Giovannoli.

Based on these pre-clinical results, the team of Nicolas Lévy conducted a clinical trial with the support of the AFM (French Association against Myopathies) and of the Ministry of Health (under the PHRC National Program) between 2008 and 2013. The trial includes 12 european patients from the Timone hospital in Marseille (monocentric, phase II, longitudinal, prospective, open-label, non-randomized clinical trial).

« The treatment resulted in weight recovery, improved bone metabolism and lower risk of cardiovascular events» discloses Annachiara De Sandre-Giovannoli. For the first time, the scientists were able to slow the progression of the disease and improve quality of life of the patients. « But unfortunately, the effects were only temporary, so we are now in search of more efficient therapeutic approaches » concludes Annachiara De Sandre-Giovannoli.

To refine their strategy, the scientists from AgiPreC and Carlos Lopez-Otin’ s laboratory first decided to build a mouse model that better recapitulated the defects seen in Progeria patients.  They introduced a mutation in the mouse Lmna gene that is equivalent to the one they had previously identified in patients, generating only one year later what is now considered to be the best Progeria mouse model available. These animals not only produce progerin by the same mechanism that young patients do, but also present with the same clinical signs, and their life expectancy is of 101 days in average (as compared to two years for a healthy mouse).

Limiting the progerin overflow

The second therapeutic route undertaken by the department consists on lowering the amount of the toxic protein in the cell. To investigate how this goal could be achieved, the scientists turned themselves to neurons.  Interestingly, although this systemic disease affects a number of organs in the body, it is not associated with cognitive impairment, suggesting that a mechanism is in place in neurons that protects them from premature aging.

The scientists established a collaboration with the team of Xavier Nissan at the I-Stem Institute, directed by Marc Peschanski, and together, they demonstrated that neurons actually express a micro-RNA that blocks a cryptic splicing site responsible for the production of progerin. This micro-RNA, now called miR-9, is overexpressed in neurons where it limits the synthesis of lamin A, and hence of progerin. Importantly, in vitro expression of miR-9 in cells derived from Progeria patients reduces the amounts of progerin and restores nuclear morphology.

« To mimic the effect of miR-9, we designed antisense vivo-morpholino oligos (short RNA molecules capped with a polymer that ensures their delivery to cells) to either block the synthesis of progerin or promote the production of normal lamin A », says Nicolas Lévy. « Upon treatment with these oligos, progeria mice displayed a significant increase in life expectancy, reaching 190 days for some of the animals ».

Building on these positive results, the researchers at AgiPreC are now testing different vectors and methods of administration to improve efficacy and safety of this procedure. In parallel, they continue their hunt for new molecules that could either limit the production of progerin or increase its degradation.

Beyond premature aging: cancer and male infertility

The department is hence looking for new therapeutic compounds, a search undertaken by combining the use of iPS cells (induced pluripotent stem cells) with high-throughput phenotypic screens (where individual compounds from a molecule collection are tested for their ability to modify one or more cellular traits). In collaboration with Xavier Nissan’s laboratory,  the department has recently demonstrated that two compounds that are derived from vitamin A (ATRA and 13-cis RA) can inhibit progerin synthesis and limit aging in iPS cells. They have also found that metformin, which is normally used to treat diabetes, reduces the production of progerin by 50% in differentiated iPS cells (differentiated into osteocytes, keratinocytes and vascular endothelial cells).

Studying pathological forms of nuclear proteins is also important for understanding not only premature aging and the links between atypical progeroïd syndromes and lipodystrophies, but also the mechanisms at work during “normal” aging. In addition, by studying the proteins that physically interact with lamins (signalling proteins, transcription factors, microfilaments, histones…), as well as protein prenylation defects, the researchers of the AgiPreC department hope to decipher mechanisms responsible for other diseases such as cancer and male infertility.

« We are interested in studying the RAS/MAPK signalling pathway, a pathway that is involved in controlling cell proliferation, survival and mobility, and whose defects are often responsible for the development of cancers », describes Sylviane Olschwang. « Several genes mutated in rasopathies, a group of progeroïd syndromes caused by mutations in the RAS/MAPK pathway, actually encode proteins that are prenylated ».   

The department is also interested in understanding the dynamics of the nuclear lamina during spermiogenesis, the final stage of spermatogenesis in which  spermatids mature into spermatozoa. « Our aim is to understand the spatio-temporal organisation of the nuclear lamina while the cell undergoes the profound structural rearrangements required to form motile spermatozoa », explains Michael Mitchell. « our working hypothesis is that defects in lamins or in proteins they are associated with might cause infertility ».

While therapeutic solutions to treat progeria patients are on the way, researchers and clinicians at the AgiPreC department have made major contributions to the diagnostics of progeroïd syndromes and have enriched patient registries with large amounts of molecular and epidemiological data. In parallel, the laboratory of Anaïs Baudot is developping systems biology approaches to identify new diagnostic or therapeutic markers, by combining data from patient samples, data from omics approaches and bioinformatics.

Elouej, S.  et al. 2020

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

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...
Nat Comm - issue: 11 - volume: 1 - pages: 4589.

Pitrez, P.  et al. 2020

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

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...
Nat Comm - issue: 1 - volume: 11 - pages: 4110.

Paci, M.  et al. 2018

The involvement of the nuclear lamina in human and rodent spermiogenesis: a systematic review

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. The NL is a component of the nuclear envelope,...
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Barthélémy, F.  et al. 2018

Muscle Cells Fix Breaches by Orchestrating a Membrane Repair Ballet

Skeletal muscle undergoes many micro-membrane lesions at physiological state. Based on their sizes and magnitude these lesions are repaired via different complexes on a specific spatio-temporal...
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Valdeolivas, A.  et al. 2018

Random Walk with Restart on Multiplex and Heterogeneous Biological Networks

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Guinde, J.  et al. 2018

Lamins in Lung Cancer: Biomarkers and Key Factors for Disease Progression through miR-9 Regulation?

Lung cancer represents the primary cause of cancer death in the world. Malignant cells identification and characterization are crucial for the diagnosis and management of patients with primary or...
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Lo Cicero, A.  et al. 2018

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

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...
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Bourgeois, P.  et al. 2018

Tricho-Hepato-Enteric Syndrome mutation update: Mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects

Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in...
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Frankel, D.  et al. 2018

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

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...
Aging Cell - issue: - volume: - pages: e12766.

Esteve, C.  et al. 2018

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three...
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Harhouri, K.  et al. 2018

An overview of treatment strategies for Hutchinson-Gilford Progeria syndrome

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...
Nucleus - issue: 1 - volume: 9 - pages: 246-257.

Elkhatib, RA.  et al. 2017

LEM-domain proteins are lost during human spermiogenesis but BAF and BAF-L persist

During spermiogenesis the spermatid nucleus is elongated, and dramatically reduced in size with protamines replacing histones to produce a highly compacted chromatin. After fertilisation, this process...
Reproduction - issue: 4 - volume: 154 - pages: 387-401.

Kaspi, E.  et al. 2017

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

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,...
PLoS ONE - issue: 8 - volume: 12 - pages: e0183136.

Harhouri, K.  et al. 2017

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

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal premature and accelerated aging disease caused by a de novo point mutation in LMNA encoding A-type lamins. Progerin, a truncated and toxic...
EMBO Mol Med - issue: 9 - volume: 9 - pages: 1294-1313.

Paci, M.  et al. 2017

Abnormal retention of nuclear lamina and disorganization of chromatin-related proteins in spermatozoa from DPY19L2-deleted globozoospermic patients

The aim of this study was to characterize the nuclear lamina (NL) and lamin chromatin-partners in spermatozoa from four DPY19L2-deleted globozoospermic patients. We tested for spermatid transcripts...
Reprod. Biomed. Online - issue: 5 - volume: 35 - pages: 562-570.

Cerino, M.  et al. 2017

Genetic Characterization of a French Cohort of GNE-mutation negative inclusion body myopathy patients with exome sequencing

INTRODUCTION: Hereditary inclusion body myopathy (hIBM) refers to a group of clinically and genetically heterogeneous diseases. The overlapping histochemical features of hIBM with other genetic...
Muscle Nerve - issue: 5 - volume: 56 - pages: 993-997.

Jallades, L.  et al. 2017

Exome sequencing identifies recurrent BCOR alterations and the absence of KLF2, TNFAIP3 and MYD88 mutations in splenic diffuse red pulp small B-cell lymphoma

Splenic diffuse red pulp lymphoma is an indolent small B-cell lymphoma recognized as a provisional entity in the World Health Organization 2008 classification. Its precise relationship to other...
Haematologica - issue: 10 - volume: 102 - pages: 1758-1766.

Bal, E.  et al. 2017

Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas

Basal cell carcinoma (BCC), the most common human cancer, results from aberrant activation of the Hedgehog signaling pathway. Although most cases of BCC are sporadic, some forms are inherited, such as...
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Nguyen, K.  et al. 2017

Molecular combing reveals complex 4q35 rearrangements in Facioscapulohumeral dystrophy

Facioscapulohumeral dystrophy (FSHD), one of the most common hereditary neuromuscular disorders, is associated with a complex combination of genetic variations at the subtelomeric 4q35 locus. As...
Hum. Mutat. - issue: 10 - volume: 38 - pages: 1432-1441.

Elkhatib, RA.  et al. 2017

Homozygous deletion of SUN5 in three men with decapitated spermatozoa

A recent study of 17 men with decapitated spermatozoa found that 8 carried two rare SUN5 alleles, and concluded that loss of SUN5 function causes the acephalic spermatozoa syndrome. Consistent with...
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Elouej, S.  et al. 2017

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

Background. Mandibular hypoplasia, deafness, progeroid features; and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a...
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Lacoste, C.  et al. 2017

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Gordon, CT.  et al. 2017

De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense...
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Ittel, A.  et al. 2016

Molecular combing: A new tool in diagnosing leukemia

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Cancer Biomark. - issue: 4 - volume: 17 - pages: 405-409.

Egesipe, A.  et al. 2016

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

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 LMNA gene that leads to the...
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Soria-Valles, C.  et al. 2016

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

BACKGROUND: Progeroid syndromes are genetic disorders that recapitulate some phenotypes of physiological ageing. Classical progerias, such as Hutchinson-Gilford progeria syndrome (HGPS), are generally...
J. Med. Genet. - issue: 11 - volume: 53 - pages: 776-785.

Lo Cicero, A.  et al. 2016

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

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...
Sci Rep - issue: - volume: 6 - pages: 34798.

Bevilacqua, J.  et al. 2016

Calpainopathy in Chile, first cases reported

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Gaillard, M.  et al. 2016

Segregation between SMCHD1 mutation, D4Z4 hypomethylation and Facio-Scapulo-Humeral Dystrophy: a case report

BACKGROUND: The main form of Facio-Scapulo-Humeral muscular Dystrophy is linked to copy number reduction of the 4q D4Z4 macrosatellite (FSHD1). In 5 % of cases, FSHD phenotype appears in the absence...
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Harhouri, K.  et al. 2016

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

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...
Cells - issue: 3 - volume: 5 - pages: .

Galant, D.  et al. 2016

A Heterozygous ZMPSTE24 Mutation Associated with Severe Metabolic Syndrome, Ectopic Fat Accumulation, and Dilated Cardiomyopathy

ZMPSTE24 encodes the only metalloprotease, which transforms prelamin into mature lamin A. Up to now, mutations in ZMPSTE24 have been linked to Restrictive Dermopathy (RD), Progeria or Mandibulo-Acral...
Cells - issue: 2 - volume: 5 - pages: 21.

Salgado, D.  et al. 2016

UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution

Whole-exome sequencing (WES) is increasingly applied to research and clinical diagnosis of human diseases. It typically results in large amounts of genetic variations. Depending on the mode of...
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Di Meglio, C.  et al. 2016

Clinical and allelic heterogeneity in a pediatric cohort of 11 patients carrying MFN2 mutation

INTRODUCTION: The Mitofusin 2 gene (MFN2), which encodes a mitochondrial membrane protein, is known to be the first cause of autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2) with early...
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Ambrosi, P.  et al. 2016

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

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Coverage analysis of lists of genes involved in heterogeneous genetic diseases following benchtop exome sequencing using the ion proton

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Nishikawa, A.  et al. 2016

Respiratory and Cardiac Function in Japanese Patients with Dysferlinopathy

Introduction: We retrospectively reviewed respiratory and cardiac function in patients with dysferlinopathy, including 2 autopsy cases with respiratory dysfunction. Methods: Subjects included 48...
Muscle Nerve - issue: 3 - volume: 53 - pages: 394-401.

Sevy, A.  et al. 2016

Improving molecular diagnosis of distal myopathies by targeted next-generation sequencing

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Blondel, S.  et al. 2016

Drug screening on Hutchinson Gilford progeria pluripotent stem cells reveals aminopyrimidines as new modulators of farnesylation

Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by a dramatic appearance of premature aging. HGPS is due to a single-base substitution in exon 11 of the LMNA gene...
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Woudt, L.  et al. 2016

Toward an Objective Measure of Functional Disability in Dysferlinopathy

Introduction: Understanding the natural history of dysferlinopathy is essential to design and quantify novel therapeutic protocols. Our aim in this study was to assess, clinically and functionally, a...
Muscle Nerve - issue: 1 - volume: 53 - pages: 49-57.

Fatehi, F.  et al. 2015

Dysferlinopathy in Iran: Clinical and genetic report

Background: Dysferlinopathy is caused by a very wide range of autosomal recessively inherited mutations of the Dysferlin gene. It causes a spectrum of muscle diseases including limb-girdle muscular...
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Vodopiutz, J.  et al. 2015

WDR73 Mutations Cause Infantile Neurodegeneration and Variable Glomerular Kidney Disease

Infantile-onset cerebellar atrophy (CA) is a clinically and genetically heterogeneous trait. Galloway-Mowat syndrome (GMS) is a rare autosomal recessive disease, characterized by microcephaly with...
Hum. Mutat. - issue: 11 - volume: 36 - pages: 1021-1028.

Ben Yaou, R.  et al. 2015

First italo-french meeting on laminopathies and other pathologies related to the nuclear envelope

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Barthelemy, F.  et al. 2015

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

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...
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Gorokhova, S.  et al. 2015

Clinical massively parallel sequencing for the diagnosis of myopathies

Massively parallel sequencing, otherwise known as high-throughput or next-generation sequencing, is rapidly gaining wide use in clinical practice due to possibility of simultaneous exploration of...
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Kergourlay, V.  et al. 2015

Comment on: A novel dysferlin-mutant pseudoexon bypassed with antisense oligonucleotides

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Nectoux, J.  et al. 2015

Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing

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Eur. J. Hum. Genet. - issue: 7 - volume: 23 - pages: 929-934.

Jobling, RK.  et al. 2015

PMPCA mutations cause abnormal mitochondrial protein processing in patients with non-progressive cerebellar ataxia

Non-progressive cerebellar ataxias are a rare group of disorders that comprise approximately 10% of static infantile encephalopathies. We report the identification of mutations in PMPCA in 17 patients...
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Puppo, F.  et al. 2015

Identification of Variants in the 4q35 Gene FAT1 in Patients with a Facioscapulohumeral Dystrophy-Like Phenotype

Facioscapulohumeralmuscular dystrophy (FSHD) is linked to copy-number reduction (N<10) of the 4q D4Z4 subtelomeric array, in association with DUX4-permissive haplotypes. This main form is indicated as...
Hum. Mutat. - issue: 4 - volume: 36 - pages: 443-453.

Sibertin-Blanc, C.  et al. 2015

Vascular Endothelial Growth Factor A c.*237C > T polymorphism is associated with bevacizumab efficacy and related hypertension in metastatic colorectal cancer

Background: No predictive marker has been yet identified for bevacizumab which is widely used in metastatic colorectal cancer. Aims: Evaluate impact of single nucleotide polymorphisms involved in...
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Elkhatib, R.  et al. 2015

Nuclear envelope remodelling during human spermiogenesis involves somatic B-type lamins and a spermatid-specific B3 lamin isoform

The nuclear lamina (NL) is a filamentous protein meshwork, composed essentially of lamins, situated between the inner nuclear membrane and the chromatin. There is mounting evidence that the NL plays a...
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Salort-Campana, E.  et al. 2015

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study

Background: Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35....
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Bartoli, M.  et al. 2014

Exome Sequencing as a Second-Tier Diagnostic Approach for Clinically Suspected Dysferlinopathy Patients

Introduction: Autosomal recessive muscular dystrophies are heterogeneous genetic disorders, with 39 genes currently implicated. Genetic diagnosis using targeted single-gene analysis by Sanger...
Muscle Nerve - issue: 6 - volume: 50 - pages: 1007-1010.

Kergourlay, V.  et al. 2014

Identification of Splicing Defects Caused by Mutations in the Dysferlin Gene

Missense, iso-semantic, and intronic mutations are challenging for interpretation, in particular for their impact in mRNA. Various tools such as the Human Splicing Finder (HSF) system could be used to...
Hum. Mutat. - issue: 12 - volume: 35 - pages: 1532-1541.

Xi, J.  et al. 2014

Clinical heterogeneity and a high proportion of novel mutations in a Chinese cohort of patients with dysferlinopathy

Background and Aims: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene. This study presents clinical features and the mutational...
Neurol. India - issue: 6 - volume: 62 - pages: 635-639.

Bonello-Palot, N.  et al. 2014

Prelamin A accumulation in endothelial cells induces premature senescence and functional impairment

Background: Defects in lamin A maturation result in premature aging syndromes and severe atherosclerosis as observed in the Hutchinson-Gilford Progeria Syndrome. In age-related atherosclerosis,...
Atherosclerosis - issue: 1 - volume: 237 - pages: 45-52.

Puppo, F.  et al. 2014

Molecular defects in FAT1 are associated to facioscapulohumeral dystrophy (FSHD)

Neuromusc. Disord. - issue: 9-10 - volume: 24 - pages: 797-798.