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.

Sánchez-Valle, J.  et al. 2017

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Sci Rep - issue: 1 - volume: 7 - pages: 4474.

Tabarés-Seisdedos, R.  et al. 2016

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Front Physiol - issue: - volume: 7 - pages: 117.

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.

Hamadou, WS.  et al. 2016

Mutational analysis of JAK2, CBL, RUNX1, and NPM1 genes in familial aggregation of hematological malignancies

Familial aggregation of hematological malignancies has been reported highlighting inherited genetic predisposition. In this study, we targeted four candidate genes: JAK2 and RUNX1 genes assuring a...
Ann. Hematol. - issue: 7 - volume: 95 - pages: 1043-1050.

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

WOS:000372530700078
Int. J. Cardiol. - issue: - volume: 209 - pages: 317-318.

Hamadou, WS.  et al. 2016

Familial hematological malignancies: ASXL1 gene investigation

Familial aggregation among patients with several hematological malignancies has been revealed. This emphasizes the importance of genetic factors. Only few genes predisposing to familial hematological...
Clin. Transl. Oncol. - issue: 4 - volume: 18 - pages: 385-390.

Sevy, A.  et al. 2016

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

WOS:000371328100020
J. Neurol. Neurosurg. Psychiatry - issue: 3 - volume: 87 - pages: 340-U116.

Grandval, P.  et al. 2016

Consideration surrounding incidental findings throughout multigene panel testing in cancer genetics

WOS:000368806900019
Clin. Genet. - issue: 2 - volume: 89 - pages: 267-268.

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...
Cell Death Dis. - issue: - volume: 7 - pages: e2105.

Roca, E.  et al. 2016

Detection of EpCAM-positive microparticles in pleural fluid: A new approach to mini-invasively identify patients with malignant pleural effusions

Pleural biomarkers allowing to mini-invasively discriminate benign from malignant pleural effusions are needed. Among potential candidates, microparticles (MPs) are extracellular vesicles that...
Oncotarget - issue: 3 - volume: 7 - pages: 3347-3356.

Didier, G.  et al. 2015

Identifying communities from multiplex biological networks

Various biological networks can be constructed, each featuring gene/protein relationships of different meanings (e.g., protein interactions or gene co-expression). However, this diversity is...
PeerJ - issue: - volume: 3 - pages: e1525.

Movahedi, M.  et al. 2015

Obesity, Aspirin, and Risk of Colorectal Cancer in Carriers of Hereditary Colorectal Cancer: A Prospective Investigation in the CAPP2 Study

Purpose In the general population, increased adiposity is a significant risk factor for colorectal cancer (CRC), but whether obesity has similar effects in those with hereditary CRC is uncertain. This...
J. Clin. Oncol. - issue: 31 - volume: 33 - pages: 3591-+.

Flobak, .  et al. 2015

Discovery of Drug Synergies in Gastric Cancer Cells Predicted by Logical Modeling

Discovery of efficient anti-cancer drug combinations is a major challenge, since experimental testing of all possible combinations is clearly impossible. Recent efforts to computationally predict drug...
PLoS Comput. Biol. - issue: 8 - volume: 11 - pages: e1004426.

Tripathi, S.  et al. 2015

The gastrin and cholecystokinin receptors mediated signaling network: a scaffold for data analysis and new hypotheses on regulatory mechanisms

BACKGROUND: The gastrointestinal peptide hormones cholecystokinin and gastrin exert their biological functions via cholecystokinin receptors CCK1R and CCK2R respectively. Gastrin, a central regulator...
BMC Syst Biol - issue: - volume: 9 - pages: 40.

Nectoux, J.  et al. 2015

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

Defects in TRIM32 were reported in limb-girdle muscular dystrophy type 2H (LGMD2H), sarcotubular myopathies (STM) and in Bardet-Biedl syndrome. Few cases have been described to date in LGMD2H/STM, but...
Eur. J. Hum. Genet. - issue: 7 - volume: 23 - pages: 929-934.

van Kuilenburg, ABP.  et al. 2015

Frequent intragenic rearrangements of DPYD in colorectal tumours

Dihydropyrimidine dehydrogenase is a crucial enzyme for the degradation of 5-fluorouracil (5FU). DPYD, which encodes dihydropyrimidine dehydrogenase, is prone to acquire genomic rearrangements because...
Pharmacogenomics J. - issue: 3 - volume: 15 - pages: 211-218.

Roca, E.  et al. 2015

Detection of procoagulant and profibrinolytic epcam-positive microparticles in pleural fluid: a new approach for the diagnosis of the tumoral origin of pleural effusions

WOS:000356426902034
J. Thromb. Haemost. - issue: - volume: 13 - pages: 215-215.

Danjou, F.  et al. 2015

A genetic score for the prediction of beta-thalassemia severity

Clinical and hematologic characteristics of beta(beta)-thalassemia are determined by several factors resulting in a wide spectrum of severity. Phenotype modulators are: HBB mutations, HBA defects and...
Haematologica - issue: 4 - volume: 100 - pages: 455-460.

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...
Mol. Hum. Reprod. - issue: 3 - volume: 21 - pages: 225-236.

Grandval, P.  et al. 2015

Genomic variations integrated database for MUTYH-associated adenomatous polyposis

WOS:000346344000004
J. Med. Genet. - issue: 1 - volume: 52 - pages: 25-27.

Joly, P.  et al. 2014

Beta-thalassemias: molecular, epidemiological, diagnostical and clinical aspects

Beta-thalassemia is one of most common autosomal recessive disorders worldwide. In France, 5 to 10 new major or intermedia forms are diagnosed annually and the global prevalence is about 500 cases....
Ann. Biol. Clin. - issue: 6 - volume: 72 - pages: 639-668.

Doyen, J.  et al. 2014

High-resolution analysis of DNA copy number alterations in rectal cancer Correlation with metastasis, survival, and mRNA expression

Background and purpose. This study aimed to determine the candidate genes and chromosomal imbalances capable of predicting occurrences of metastasis in patients with rectal cancer. Patients and...
Strahlenther. Onkol. - issue: 11 - volume: 190 - pages: 1028-1036.

Bushby, K.  et al. 2014

Ataluren Treatment of Patients with Nonsense Mutation Dystrophinopathy

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in...
Muscle Nerve - issue: 4 - volume: 50 - pages: 477-487.

Yahiaoui, OI.  et al. 2014

Constitutive AKT activation in follicular lymphoma

Background: The phosphoinositide 3-kinase (PI3K) pathway is involved in the growth of various human cancers, including lymphoid malignancies. However its role in the pathogenesis of follicular...
BMC Cancer - issue: - volume: 14 - pages: 565.

Hadj-Rabia, S.  et al. 2014

A New Lamin A Mutation Associated with Acrogeria Syndrome

WOS:000339126100031
J. Invest. Dermatol. - issue: 8 - volume: 134 - pages: 2274-2277.

Badens, C.  et al. 2014

Complex Diagnostics in Hemoglobinopathies

WOS:000337244300037
Int. J. Lab. Hematol. - issue: - volume: 36 - pages: 15-16.

Thompson, BA.  et al. 2014

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for...
Nature Genet. - issue: 2 - volume: 46 - pages: 107-+.

Ibáñez, K.  et al. 2014

Molecular evidence for the inverse comorbidity between central nervous system disorders and cancers detected by transcriptomic meta-analyses

There is epidemiological evidence that patients with certain Central Nervous System (CNS) disorders have a lower than expected probability of developing some types of Cancer. We tested here the...
PLoS Genet. - issue: 2 - volume: 10 - pages: e1004173.

Beau-Faller, M.  et al. 2014

A Multicenter Blinded Study Evaluating EGFR and KRAS Mutation Testing Methods in the Clinical Non-Small Cell Lung Cancer Setting-IFCT/ERMETIC2 Project Part 1 Comparison of Testing Methods in 20 French Molecular Genetic National Cancer Institute Platforms

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors have limited use as first-line treatment for mutated EGFR metastatic non-small cell lung cancer. The French National Cancer Institute...
J. Mol. Diagn. - issue: 1 - volume: 16 - pages: 45-55.

Ozcan, D.  et al. 2013

A Collodion Baby with Facial Dysmorphism, Limb Anomalies, Pachygyria and Genital Hypoplasia: A Mild Form of Neu-Laxova Syndrome or a New Entity?

Neu-Laxova syndrome is a rare, lethal, autosomal recessive disorder characterized by intrauterine growth retardation, central nervous system anomalies, skin findings, such as ichthyosis, edema,...
Ann. Dermatol. - issue: 4 - volume: 25 - pages: 483-488.

Pujol, P.  et al. 2013

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in...
Breast Cancer Res. Treat. - issue: 1 - volume: 141 - pages: 135-144.

Spinelli, L.  et al. 2013

Clust&See: a Cytoscape plugin for the identification, visualization and manipulation of network clusters

BACKGROUND AND SCOPE: Large networks, such as protein interaction networks, are extremely difficult to analyze as a whole. We developed Clust&See, a Cytoscape plugin dedicated to the identification,...
BioSystems - issue: 2 - volume: 113 - pages: 91-95.

Zufferey, F.  et al. 2013

Acro-osteolysis, keloid like-lesions, distinctive facial features, and overgrowth: Two newly recognized patients with premature aging syndrome, penttinen type

We report on two unrelated patients with a rare progeroid syndrome first described by Penttinen. Patients presented with prematurely aged appearance, delayed dental development, acro-osteolysis,...
Am. J. Med. Genet. A - issue: 7 - volume: 161A - pages: 1786-1791.

Grandval, P.  et al. 2013

Design of a Core Classification Process for DNA Mismatch Repair Variations of A Priori Unknown Functional Significance

WOS:000319278500016
Hum. Mutat. - issue: 6 - volume: 34 - pages: 920-922.

Neri, M.  et al. 2013

A patient with limb girdle muscular dystrophy carries a TRIM32 deletion, detected by a novel CGH array, in compound heterozygosis with a nonsense mutation

Limb girdle muscular dystrophy 2H is a rare autosomal recessive muscular dystrophy, clinically highly variable, caused by mutations in the TRIM32 gene. Here we describe a 35-years-old who experienced...
Neuromusc. Disord. - issue: 6 - volume: 23 - pages: 478-482.

Milano, G.  et al. 2013

A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status

WOS:000335419601331
J. Clin. Oncol. - issue: 15 - volume: 31 - pages: .

Andre, F.  et al. 2013

Array CGH and DNA sequencing to personalize targeted treatment of metastatic breast cancer (MBC) patients (pts): A prospective multicentric trial (SAFIR01)

WOS:000335419600016
J. Clin. Oncol. - issue: 15 - volume: 31 - pages: .

Oudot, C.  et al. 2013

Desmoid tumors in children: current strategy

Desmoid tumor (DT) or aggressive fibromatosis is a histologically benign-appearing neoplasms of the soft tissues, arising from connective tissues, the fascial sheaths and musculoaponevrotic structures...
Bull. Cancer - issue: 5 - volume: 100 - pages: 518-528.

Marisa, L.  et al. 2013

Gene Expression Classification of Colon Cancer into Molecular Subtypes: Characterization, Validation, and Prognostic Value

Background: Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical...
PLos Med. - issue: 5 - volume: 10 - pages: e1001453.

Agouti, I.  et al. 2013

Analytical evaluation of the Capillarys 2 Flex piercing for routine haemoglobinopathies diagnosis

To evaluate the analytical performance of a new capillary electrophoresis instrument, the Capillarys 2 Flex piercing (Sebia, France), allowing the separation and quantitative estimation of the...
Int. J. Lab. Hematol. - issue: 2 - volume: 35 - pages: 217-221.

Rahner, N.  et al. 2013

Clinical utility gene card for: Lynch syndrome (MLH1, MSH2, MSH6, PMS2, EPCAM) - update 2012

WOS:000312492500001
Eur. J. Hum. Genet. - issue: 1 - volume: 21 - pages: .

Herbaux, C.  et al. 2012

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Acquired alpha-thalassemia (alpha-thal) myelodysplastic syndrome (ATMDS) is a rare acquired syndrome characterized by a somatic point mutation in the ATRX gene in patients with chronic myeloid...
Hemoglobin - issue: 6 - volume: 36 - pages: 581-585.

Mathers, JC.  et al. 2012

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Background Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of...
Lancet Oncol. - issue: 12 - volume: 13 - pages: 1242-1249.

Grandval, P.  et al. 2012

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Fam. Cancer - issue: 4 - volume: 11 - pages: 681-683.

Eyrnard, B.  et al. 2012

Diagnostic strategy for limb-girdle muscular dystrophies

Limb-girdle muscular dystrophies represent a major chapter of genetic myopathies. Many different entities have been identified, most of them with recessive transmission, a minority with dominant...
Rev. Neurol. - issue: 12 - volume: 168 - pages: 919-926.

Doubaj, Y.  et al. 2012

An inherited LMNA gene mutation in atypical Progeria syndrome

HutchinsonGilford Progeria syndrome (HGPS) is a rare genetic disorder, characterized by several clinical features that begin in early childhood, recalling an accelerated aging process. The diagnosis...
Am. J. Med. Genet. A - issue: 11 - volume: 158A - pages: 2881-2887.

Laibe, S.  et al. 2012

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OMICS - issue: 10 - volume: 16 - pages: 560-565.

De Sandre-Giovannoli, A.  et al. 2012

Antisense based therapeutic approaches in Hutchinson-Gilford Progeria

WOS:000310364400085
Hum. Gene Ther. - issue: 10 - volume: 23 - pages: A27-A27.

Grandval, P.  et al. 2012

Colon-specific phenotype in Lynch syndrome associated with EPCAM deletion

WOS:000305129600017
Clin. Genet. - issue: 1 - volume: 82 - pages: 97-99.

Bertucci, F.  et al. 2012

8q24 Cancer Risk Allele Associated with Major Metastatic Risk in Inflammatory Breast Cancer

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PLoS One - issue: 5 - volume: 7 - pages: e37943.

Levy, N.  et al. 2012

Development of synergies and partnerships on rare diseases: Model of a scientific cooperation foundation

WOS:000305168100008
Presse Med. - issue: - volume: 41 - pages: S23-S25.

Ayme, S.  et al. 2012

Conclusions of RARE 2011 and prospects for RARE 2013

WOS:000305168100023
Presse Med. - issue: - volume: 41 - pages: S65-S66.

Compagnone, M.  et al. 2012

KRAS Mutation Spectrum Notably Diverges between Non-small Cell Lung and Colorectal Carcinomas

WOS:000301866500026
J. Thorac. Oncol. - issue: 4 - volume: 7 - pages: 773-774.

Birnbaum, DJ.  et al. 2012

Expression Profiles in Stage II Colon Cancer According to APC Gene Status

Colorectal cancer is one of the most common cancers in the world. Histoclinical staging is efficient, but combination with molecular markers may improve the classification of stage II cancers. Several...
Transl. Oncol. - issue: 2 - volume: 5 - pages: 72-76.

Sakr, L.  et al. 2012

Cytology-based treatment decision in primary lung cancer: Is it accurate enough?

Accurate distinction of lung cancer types has become increasingly important as recent trials have shown differential response to chemotherapy among non-small cell lung carcinoma (NSCLC) subtypes....
Lung Cancer - issue: 3 - volume: 75 - pages: 293-299.

Kichine, E.  et al. 2012

HSFY genes and the P4 palindrome in the AZFb interval of the human Y chromosome are not required for spermatocyte maturation

BACKGROUND: Recurrent AZFb deletions on the human Y chromosome are associated with an absence of ejaculated spermatozoa consequent to a meiotic maturation arrest that prevents the progression of germ...
Hum. Reprod. - issue: 2 - volume: 27 - pages: 615-624.

Maalouf, D.  et al. 2012

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Background: Focal dermal hypoplasia (also known as Goltz syndrome) is an X-linked dominant syndrome characterized by patchy hypoplastic skin with soft-tissue, skeletal, dental, and ocular defects that...
Arch. Dermatol. - issue: 1 - volume: 148 - pages: 85-88.

Faguer, S.  et al. 2011

A 10 Mb duplication in chromosome band 5q31.3-5q33.1 associated with late-onset lipodystrophy, ichthyosis, epilepsy and glomerulonephritis

We report here a 44 years-old patient with late-onset partial lipodystrophy, mental retardation, epilepsy, ichtyosis and glomerulonephritis, carrying a 10 Mb duplication of the chromosome...
Eur. J. Med. Genet. - issue: 3 - volume: 54 - pages: 310-313.

Aubourg, P.  et al. 2005

Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3) locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes

WOS:000227470300010
J. Med. Genet. - issue: 3 - volume: 42 - pages: 253-259.