Genetics, Gene Therapy & Genetic Disease
- AAV‐mediated gene therapy as a strategy to fight obesity and metabolic diseases
The fibroblast growth factor 21 (FGF21) is a member of the FGF superfamily that now comprises 22 members identified in humans. Unlike the canonical role of most FGF family members, FGF21 is released into the circulation and acts as an endocrine hormone by binding with low affinity to FGF receptors (FGFRs) as well as to the co‐receptor β‐klotho in the target cells to trigger the ERK1/2 and MAPKs signaling pathways. Described initially as a hepatokine, subsequent studies identified significant amounts of FGF21 transcript in the pancreas, the adipose tissue, and the skeletal muscle. FGF21 expression is highly regulated by environmental stimuli such as starvation, ketogenic diet, cold exposure, and exercise.
See also: Jimenez et al (August 2018)
In this News & Views article, Kajimura and Sponton discuss the advantages and therapeutic benefits of considering FGF21 gene therapy against obesity and metabolic disorders.
EMBO Mol Med (2018) 10: e9431
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- mitoTev‐TALE: a monomeric DNA editing enzyme to reduce mutant mitochondrial DNA levels
- Claudia V Pereira1,
- Sandra R Bacman1,
- Tania Arguello1,
- Ugne Zekonyte1,
- Sion L Williams1,
- David R Edgell2 and
- Carlos T Moraes (cmoraes{at}med.miami.edu)*,1
- 1Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
- 2Department of Biochemistry, Schulich School of Medicine and Dentistry University of Western Ontario, London, ON, Canada
- ↵*Corresponding author. Tel: +1 305 243 5858; E‐mail: cmoraes{at}med.miami.edu
This work describes the development of a mitochondrial‐targeted DNA editing enzyme that can specifically cleave the MERRF m.8344A>G mtDNA mutation. The novel feature of this enzyme is that it is monomeric, in contrast to mitoTALEN and mitoZFN, which are heterodimeric.
Synopsis
This work describes the development of a mitochondrial‐targeted DNA editing enzyme that can specifically cleave the MERRF m.8344A>G mtDNA mutation. The novel feature of this enzyme is that it is monomeric, in contrast to mitoTALEN and mitoZFN, which are heterodimeric.
The homing endonuclease I‐TevI was fused to the N‐terminus of a TALE motif that binds specifically to the mtDNA MERRF m.8344A>G site.
A mitochondrial targeting sequence and a FLAG tag were also added to the N‐terminus.
When MERRF cells harboring heteroplasmic mutant mtDNA were transfected with mitoTev‐TALE there was a reduction in mutant mtDNA by approximately 20%.
The monomeric nature of this reagent should facilitate packaging into AAV vectors.
EMBO Mol Med (2018) e8084
- Received May 27, 2018.
- Revision received June 18, 2018.
- Accepted June 21, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- LETM1 couples mitochondrial DNA metabolism and nutrient preference
- Romina Durigon1,
- Alice L Mitchell1,†,
- Aleck WE Jones1,†,
- Andreea Manole2,3,
- Mara Mennuni1,
- Elizabeth MA Hirst4,
- Henry Houlden2,3,
- Giuseppe Maragni5,
- Serena Lattante5,
- Paolo Niccolo’ Doronzio5,
- Ilaria Dalla Rosa1,
- Marcella Zollino5,
- Ian J Holt1,6,7 and
- Antonella Spinazzola (a.spinazzola{at}ucl.ac.uk)*,1,2
- 1Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK
- 2MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
- 3Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
- 4MRC Mill Hill Laboratory, London, UK
- 5Institute of Genomic Medicine, Catholic University, Rome, Italy
- 6Biodonostia Health Research Institute, San Sebastián, Spain
- 7IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- ↵*Corresponding author. Tel: +44 20 77940500 ext 33009; Fax: +44 20 7472 682; E‐mail: a.spinazzola{at}ucl.ac.uk
↵† These authors contributed equally to this work
The mitochondrial inner membrane protein LETM1 regulates mitochondrial DNA metabolism according to nutrient availability, which suggests that in the Wolf‐Hirschhorn syndrome and a range of other mitochondrial disorders, dietary control could impact disease development and progression.
Synopsis
The mitochondrial inner membrane protein LETM1 regulates mitochondrial DNA metabolism according to nutrient availability, which suggests that in the Wolf‐Hirschhorn syndrome and a range of other mitochondrial disorders, dietary control could impact disease development and progression.
Nutrients configure mitochondrial nucleoprotein complexes for energy production; for glucose such adaptation is mediated by LETM1.
LETM1 and pyruvate dehydrogenase (PDH) are physically associated with mitochondrial nucleoprotein complexes.
Monoallelic deletion of LETM1 inactivates PDH and causes aggregation of mitochondrial nucleoids.
LETM1 haploinsufficiency permits proliferation on a strict ketone body growth regime, whereas control cells undergo irreversible mitochondrial DNA aggregation and cell death.
Mitochondrial translation and ribosome maintenance in human cells requires LETM1 when the organelles utilize glucose and pyruvate.
EMBO Mol Med (2018) e8550
- Received October 2, 2017.
- Revision received June 7, 2018.
- Accepted June 14, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Aberrant regulation of the GSK‐3β/NRF2 axis unveils a novel therapy for adrenoleukodystrophy
- Pablo Ranea‐Robles1,2,
- Nathalie Launay1,2,
- Montserrat Ruiz1,2,
- Noel Ylagan Calingasan3,
- Magali Dumont4,
- Alba Naudí5,
- Manuel Portero‐Otín5,
- Reinald Pamplona5,
- Isidre Ferrer6,7,8,9,
- M Flint Beal3,
- Stéphane Fourcade (sfourcade{at}idibell.cat)*,1,2 and
- Aurora Pujol (apujol{at}idibell.cat)*,1,2,10
- 1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat Barcelona, Spain
- 2CIBERER U759, Center for Biomedical Research on Rare Diseases ISCIII, Barcelona, Spain
- 3Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, USA
- 4UMR S 1127, Inserm, U1127, CNRS, UMR 7225, Institut du Cerveau et de la Moelle épinière, Sorbonne Universités, UPMC Université Paris 06, Paris, France
- 5Experimental Medicine Department, University of Lleida‐IRB Lleida, Lleida, Spain
- 6Department of Pathology and Experimental Therapeutics, Faculty of Medicine, University of Barcelona, L'Hospitalet de Llobregat Barcelona, Spain
- 7Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), ISCIII, Madrid, Spain
- 8Institute of Neurosciences, University of Barcelona, Barcelona, Spain
- 9IDIBELL‐Bellvitge University Hospital, L'Hospitalet de Llobregat, Spain
- 10Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain
- ↵*
Corresponding author. Tel: +34 932 60 71 37; Fax: +34 932 60 74 14; E‐mail: sfourcade{at}idibell.cat
Corresponding author. Tel: +34 932 60 71 37; Fax: +34 932 60 74 14; E‐mail: apujol{at}idibell.cat
This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option.
Synopsis
This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option.
NRF2‐mediated antioxidant response is impaired in X‐linked adrenoleukodystrophy (X‐ALD) mouse spinal cord and human fibroblasts.
Aberrant GSK‐3β activity is responsible for the NRF2 blunted response against oxidative stress in X‐ALD fibroblasts.
Molecular defects present in the X‐ALD mouse model are rescued after oral treatment with dimethyl fumarate, an NRF2 activator in current use for multiple sclerosis.
Axonal degeneration and locomotor impairment in X‐ALD mouse model are prevented with dimethyl fumarate, indicating its therapeutic potential for X‐ALD patients.
EMBO Mol Med (2018) 10: e8604
- Received October 20, 2017.
- Revision received June 6, 2018.
- Accepted June 12, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- FGF21 gene therapy as treatment for obesity and insulin resistance
- Veronica Jimenez1,2,3,†,
- Claudia Jambrina1,2,3,†,
- Estefania Casana1,2,3,
- Victor Sacristan1,2,3,
- Sergio Muñoz1,2,3,
- Sara Darriba1,2,3,
- Jordi Rodó1,2,3,
- Cristina Mallol1,2,3,
- Miquel Garcia1,2,3,
- Xavier León1,2,3,
- Sara Marcó1,2,3,
- Albert Ribera1,2,3,
- Ivet Elias1,2,3,
- Alba Casellas1,2,3,
- Ignasi Grass1,2,3,
- Gemma Elias1,2,3,
- Tura Ferré1,3,
- Sandra Motas1,2,3,
- Sylvie Franckhauser1,3,
- Francisca Mulero3,4,
- Marc Navarro1,3,5,
- Virginia Haurigot1,2,3,
- Jesus Ruberte1,3,5 and
- Fatima Bosch (fatima.bosch{at}uab.es)*,1,2,3
- 1Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, Bellaterra, Spain
- 2Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain
- 3CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
- 4Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- 5Department of Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
- ↵*Corresponding author. Tel: +34 93 581 41 82; E‐mail: fatima.bosch{at}uab.es
↵† These authors contributed equally to this work
This study describes the use of adeno‐associated viral (AAV) vectors to achieve long‐term production of fibroblast growth factor 21 (FGF21) to treat obesity and insulin resistance. AAV‐FGF21 gene transfer to healthy animals also prevented age‐associated weight gain and insulin resistance.
Synopsis
This study describes the use of adeno‐associated viral (AAV) vectors to achieve long‐term production of fibroblast growth factor 21 (FGF21) to treat obesity and insulin resistance. AAV‐FGF21 gene transfer to healthy animals also prevented age‐associated weight gain and insulin resistance.
A one‐time administration of an AAV vector encoding FGF21 counteract obesity and insulin resistance for more than a year.
The approach works in two different animal models of obesity, induced either by diet or genetic mutations.
Administration of AAV‐FGF21 to healthy animals promotes healthy aging.
AAV‐FGF21 pharmacological effects are demonstrated after genetic engineering of 3 different tissues (liver, adipose tissue and skeletal muscle).
FGF21 gene therapy holds great translational potential in the fight against insulin resistance, T2D, obesity and related comorbidities.
EMBO Mol Med (2018) 10: e8791
- Received December 18, 2017.
- Revision received June 8, 2018.
- Accepted June 14, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Brain‐targeted stem cell gene therapy corrects mucopolysaccharidosis type II via multiple mechanisms
- Hélène FE Gleitz1,
- Ai Yin Liao1,
- James R Cook1,
- Samuel F Rowlston1,
- Gabriella MA Forte1,
- Zelpha D'Souza1,
- Claire O'Leary1,
- Rebecca J Holley1 and
- Brian W Bigger (brian.bigger{at}manchester.ac.uk)*,1
- 1Stem Cell and Neurotherapies, Division of Cell Matrix Biology & Regenerative Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- ↵*Corresponding author. Tel: +44 161 3060516; E‐mail: brian.bigger{at}manchester.ac.uk
The use of an ApoEII‐tag to increase uptake of the lysosomal enzyme IDS greatly improved the efficacy of hematopoietic stem cell gene therapy in MPS II mice, providing encouraging therapeutic promise to treat the severe neurodegeneration seen in MPS II patients, for which there is currently no cure.
Synopsis
The use of an ApoEII‐tag to increase uptake of the lysosomal enzyme IDS greatly improved the efficacy of hematopoietic stem cell gene therapy in MPS II mice, providing encouraging therapeutic promise to treat the severe neurodegeneration seen in MPS II patients, for which there is currently no cure.
Lentiviral mediated delivery of IDS.ApoEII following hematopoietic stem cell gene therapy was superior to delivery of unmodified IDS.
LV.IDS.ApoEII increased IDS enzyme activity in non‐hematopoietic organs and restored normal skeletal development.
IDS.ApoEII delivered into the brain of MPS II mice through corrected monocyte‐derived macrophages normalized lysosomal storage of glycosaminoglycans and restored glycosaminoglycan sulfation patterning.
IDS.ApoEII rectified behavioral abnormalities and corrected global neuro‐inflammation and neuro‐pathology.
IDS.ApoEII shows increased uptake and transcytosis by brain endothelial cells.
EMBO Mol Med (2018) 10: e8730
- Received November 29, 2017.
- Revision received May 10, 2018.
- Accepted May 16, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Response to growth hormone in patients with RNPC3 mutations
- Gabriel Á Martos‐Moreno1,2,3,4,
- Lourdes Travieso‐Suárez1,2,3,
- Jesús Pozo‐Román1,2,3,4,
- María T Muñoz‐Calvo1,2,3,4,
- Julie A Chowen1,2,3,4,5,
- Mikko J Frilander6,
- Luis A Pérez‐Jurado7,8,9,
- Federico G Hawkins10 and
- Jesús Argente (jesus.argente{at}uam.es) (jesus.argente{at}fundacionendo.org)1,2,3,4,5
- 1Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
- 2Instituto de Investigación La Princesa, Madrid, Spain
- 3Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain
- 4Instituto de Salud Carlos III, CIBER de Fisiopatologia de la Obesidad y Nutriciόn (CIBEROBN), Madrid, Spain
- 5IMDEA Food Institute, CEIUAM+CSIC, Madrid, Spain
- 6Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- 7Genetics Unit, Universitat Pompeu Fabra, Barcelona, Spain
- 8Instituto de Salud Carlos III, Hospital del Mar Research Institute (IMIM) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
- 9SA Clinical Genetics, Women's and Children's Hospital & University of Adelaide, Adelaide, SA, Australia
- 10Diabetes and Bone Research Center, Institute i + 12, Complutense University and Hospital 12 de Octubre, Madrid, Spain
After 6 years of Growth Hormone (GH) therapy, three patients with a defect in minor spliceosome mRNA processing leading to an incompletely understood GH deficit present with excellent auxological response and improvement in the bone mineral density and trabecular bone structure.
EMBO Mol Med (2018) 10: e9143
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- A novel CHCHD10 mutation implicates a Mia40‐dependent mitochondrial import deficit in ALS
- Carina Lehmer1,
- Martin H Schludi1,2,
- Linnea Ransom1,
- Johanna Greiling1,
- Michaela Junghänel1,
- Nicole Exner3,
- Henrick Riemenschneider1,
- Julie van der Zee4,5,
- Christine Van Broeckhoven4,5,
- Patrick Weydt6,
- Michael T Heneka6,7 and
- Dieter Edbauer (dieter.edbauer{at}dzne.de)*,1,2
- 1German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany
- 2Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
- 3Biomedical Center (BMC), Biochemistry, Ludwig‐Maximilians‐Universität München, Munich, Germany
- 4Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium
- 5Laboratory of Neurogenetics, Institute Born‐Bunge, University of Antwerp, Antwerp, Belgium
- 6Department of Neurodegenerative Diseases and Geriatric Psychiatry, Bonn University Hospital, Bonn, Germany
- 7German Center for Neurodegenerative Disease (DZNE) Bonn, Bonn, Germany
- ↵*Corresponding author. Tel: +49 89 440046 510; E‐mail: dieter.edbauer{at}dzne.de
Mutations in the mitochondrial protein CHCHD10 have been linked to amyotrophic lateral sclerosis, but incomplete penetrance has raised concerns about pathogenicity. The identification of a novel mutation (Q108P) in a young patient with aggressive disease reveals a loss‐of‐function mechanism.
Synopsis
Mutations in the mitochondrial protein CHCHD10 have been linked to amyotrophic lateral sclerosis, but incomplete penetrance has raised concerns about pathogenicity. The identification of a novel mutation (Q108P) in a young patient with aggressive disease reveals a loss‐of‐function mechanism.
CHCHD10 Q108P disrupts mitochondrial import resulting in reduced protein half‐life time.
CHCHD10 reduction results in smaller spare respiratory capacity.
Mia40 imports CHCHD10 into mitochondria through disulfide‐bond formation in the CHCH domain.
Overexpression of Mia40 restores mitochondrial targeting of CHCHD10 Q108P.
EMBO Mol Med (2018) 10: e8558
- Received October 14, 2017.
- Revision received April 13, 2018.
- Accepted April 18, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- mtDNA heteroplasmy level and copy number indicate disease burden in m.3243A>G mitochondrial disease
- John P Grady1,4,†,
- Sarah J Pickett (sarah.pickett{at}ncl.ac.uk)*,1,†,
- Yi Shiau Ng1,
- Charlotte L Alston1,2,
- Emma L Blakely1,2,
- Steven A Hardy1,2,
- Catherine L Feeney1,
- Alexandra A Bright1,
- Andrew M Schaefer1,
- Gráinne S Gorman1,
- Richard JQ McNally3,
- Robert W Taylor1,2,
- Doug M Turnbull1 and
- Robert McFarland (robert.mcfarland{at}ncl.ac.uk)*,1
- 1Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
- 2NHS Highly Specialised Mitochondrial Diagnostic Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- 3Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
- 4Present Address: Kinghorn Centre for Clinical Genomics, Garvan Institute, Sydney, NSW, Australia
- ↵*
Corresponding author. Tel: +44 191 2085397; E‐mail: sarah.pickett{at}ncl.ac.uk
Corresponding author. Tel: +44 191 2820340; E‐mail: robert.mcfarland{at}ncl.ac.uk
↵† These authors contributed equally to this work
The m.3243A>G pathogenic mtDNA variant is associated with a highly heterogeneous multisystem disorder and varying mutation levels across tissues. In this study, mutation levels were characterised in three commonly sampled tissues ‐ blood, urine, skeletal muscle ‐ and correlated with disease burden.
Synopsis
The m.3243A>G pathogenic mtDNA variant is associated with a highly heterogeneous multisystem disorder and varying mutation levels across tissues. In this study, mutation levels were characterised in three commonly sampled tissues ‐ blood, urine, skeletal muscle ‐ and correlated with disease burden.
Urine m.3243A>G heteroplasmy levels display more variability than blood levels and must be corrected for a ˜20% lower level in females.
Blood m.3243A>G heteroplasmy levels must be corrected for a decline of ˜2.3% per year.
Disease burden and progression are more strongly associated with blood m.3243A>G heteroplasmy levels than urine levels.
27% of the variance in disease burden can be attributed to blood m.3243A>G heteroplasmy and age.
Age, m.3243A>G heteroplasmy level and mtDNA copy number in skeletal muscle explain 40% of the variance in disease burden.
EMBO Mol Med (2018) 10: e8262
- Received July 14, 2017.
- Revision received March 29, 2018.
- Accepted April 4, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- PATL2 is a key actor of oocyte maturation whose invalidation causes infertility in women and mice
- Marie Christou‐Kent1,
- Zine‐Eddine Kherraf1,
- Amir Amiri‐Yekta1,2,3,
- Emilie Le Blévec1,
- Thomas Karaouzène1,
- Béatrice Conne4,
- Jessica Escoffier1,
- Said Assou5,
- Audrey Guttin6,
- Emeline Lambert1,
- Guillaume Martinez1,2,7,
- Magalie Boguenet1,
- Selima Fourati Ben Mustapha8,
- Isabelle Cedrin Durnerin9,
- Lazhar Halouani8,
- Ouafi Marrakchi8,
- Mounir Makni8,
- Habib Latrous8,
- Mahmoud Kharouf8,
- Charles Coutton1,2,7,
- Nicolas Thierry‐Mieg10,
- Serge Nef4,
- Serge P Bottari1,
- Raoudha Zouari8,
- Jean Paul Issartel6,
- Pierre F Ray1,2,† and
- Christophe Arnoult (christophe.arnoult{at}univ-grenoble-alpes.fr)*,1,†
- 1Genetics, Epigenetics and Therapies of Infertility, Institute for Advanced Biosciences, Inserm U1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France
- 2UM GI‐DPI, CHU de Grenoble, Grenoble, France
- 3Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
- 4Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland
- 5IRMB, INSERM U1183, CHRU Montpellier, Université Montpellier, Montpellier, France
- 6Grenoble Neuroscience Institute, INSERM 1216, Université Grenoble Alpes, Grenoble, France
- 7UM de Génétique Chromosomique, CHU de Grenoble, Grenoble, France
- 8Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, Tunis, Tunisia
- 9Service de Médecine de la Reproduction, Centre Hospitalier Universitaire Jean Verdier, Assistance Publique ‐ Hôpitaux de Paris, Bondy, France
- 10Univ. Grenoble Alpes/CNRS, TIMC‐IMAG CNRS UMR 5525, Grenoble, France
- ↵*Corresponding author. Tel: +33 476 637 408; E‐mail: christophe.arnoult{at}univ-grenoble-alpes.fr
↵† These authors contributed equally to this work as senior authors
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
Synopsis
A novel mutation in the gene PATL2 causes oocyte maturation arrest at the germinal vesicle (GV) stage. In mice, Patl2 deficiency during oocyte growth modifies the global transcriptional landscape of GV oocytes, causing dramatic defects and hampering normal maturation.
In a cohort of 23 infertile women from North Africa with oocyte meiotic deficiency (OMD), a truncating mutation in the gene PATL2, encoding an RNA‐binding protein, was identified in 26% of patients.
Patl2 knockout female mice presented severe subfertility, confirming the human diagnostic. Patl2 knockout mouse oocytes could progress to the MII stage, however with numerous morphological defects hampering normal fertilisation and development.
Patl2 is not detectable in primordial follicle oocytes, but is strongly expressed during oocyte growth and remains detectable at least until the MII stage.
Patl2 has a unique expression pattern from primordial follicle‐stage to MII‐stage oocytes and did not colocalise with Cpeb1, Msy2 or Ddx6 known to stabilise mRNA during oocyte growth.
Patl2 deficiency leads to a down or up‐regulation of a subset of mRNAs encoding proteins which are crucial for oocyte meiotic progression and early embryonic development, with no effect on the GV‐MII transition.
EMBO Mol Med (2018) 10: e8515
- Received September 21, 2017.
- Revision received March 12, 2018.
- Accepted March 19, 2018.
- © 2018 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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