Time filter

Source Type

Rome, Italy

Richer J.,Ottawa Hospital Research Institute | Laberge A.-M.,Medical Genetics
Canadian Journal of Cardiology

The knowledge surrounding the genetic etiologies of familial aortopathies and familial thoracic aortic aneurysms and dissections has greatly expanded over the past few years. However, despite these advances, the underlying molecular etiology remains unidentified in most families with nonsyndromic familial aortopathies, and in a subset of families with syndromic aortopathies. In these families we cannot offer a genetic test to establish which family members are at risk. Although the general consensus has been to clinically follow all at-risk family members on the basis of family history, it remains unclear at the age at which to initiate clinical surveillance and the frequency which to screen asymptomatic relatives, whether or not a genetic etiology has been established in the family. These questions are particularly troublesome in a pediatric context where the risks of screening are potentially higher and the likelihood that such screening will provide immediate benefits is often lower than in adults. In this report we aim to: (1) provide clinicians with a framework within which to evaluate risks and benefits of screening asymptomatic pediatric patients for a family history of thoracic aortic aneurysms and dissections; and (2) provide a potential approach for patients (a) in whose family a disease-causing mutation has been identified, (b) patients in whose family the proband is syndromic, but does not have an identified disease-causing mutation, and (c) patients in whose family the proband is nonsyndromic and does not have an identified disease-causing mutation. © 2016 Canadian Cardiovascular Society. Source

Alrahbeni T.,University of Aberdeen | Sartor F.,University of Aberdeen | Anderson J.,University of Aberdeen | Miedzybrodzka Z.,Medical Genetics | And 2 more authors.
Molecular Brain

Background: Mutation in the UPF3B gene on chromosome X is implicated in neurodevelopmental disorders including X-linked intellectual disability, autism and schizophrenia. The protein UPF3B is involved in the nonsense-mediated mRNA decay pathway (NMD) that controls mRNA stability and functions in the prevention of the synthesis of truncated proteins. Results: Here we show that NMD pathway components UPF3B and UPF1 are down-regulated during differentiation of neural stem cells into neurons. Using tethered function assays we found that UPF3B missense mutations described in families with neurodevelopmental disorders reduced the activity of UPF3B protein in NMD. In neural stem cells, UPF3B protein was detected in the cytoplasm and in the nucleus. Similarly in neurons, UPF3B protein was detected in neurites, the somatic cytoplasm and in the nucleus. In both cell types nuclear UPF3B protein was enriched in the nucleolus. Using GFP tagged UPF3B proteins we found that the missense mutations did not affect the cellular localisation. Expression of missense mutant UPF3B disturbed neuronal differentiation and reduced the complexity of the branching of neurites. Neuronal differentiation was similarly affected in the presence of the NMD inhibitor Amlexanox. The expression of mutant UPF3B proteins lead to a subtle increase in mRNA levels of selected NMD targets. Conclusions: Together our findings indicate that, despite the down-regulation of NMD factors, functional NMD is critical for neuronal differentiation. We propose that the neurodevelopmental phenotype of UPF3B missense mutation is caused by impairment of NMD function altering neuronal differentiation. © 2015 Alrahbeni et al.; licensee BioMed Central. Source

Costello syndrome (OMIM# 218040) is a distinctive rare multisystem disorder comprising a characteristic coarse facial appearance, intellectual disabilities, and tumor predisposition. Although the diagnosis can be suspected clinically, confirmation requires identification of a heterozygous mutation in the proto-oncogene HRAS. In contrast to somatic oncogenic mutations in neoplasia, the Costello syndrome changes are typically introduced in the paternal germline. The predicted amino acid substitutions allow for constitutive or prolonged activation of the HRAS protein, resulting in dysregulation of the Ras/mitogen activated protein kinase pathway. Dysregulation of this signaling pathway is the disease mechanism shared among Costello syndrome and other rasopathies, including neurofibromatosis type 1, Noonan syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. The Ras/mitogen activated protein kinase pathway governs cell proliferation and differentiation, and its dysregulation affects cardiac and brain development, accounting for the significant overlap in physical and developmental differences and common medical problems among rasopathies. Unlike the genetically heterogeneous Noonan syndrome and cardio-facio-cutaneous syndrome, Costello syndrome is caused by HRAS mutations only. Patients, clinicians, and researchers may benefit from a multidisciplinary rasopathy clinic, which serves patients with more common conditions such as Noonan syndrome and neurofibromatosis and those affected by rare conditions such as Costello syndrome. © American College of Medical Genetics and Genomics. Source

Messinger Y.H.,Pediatric Hematology Oncology | Mendelsohn N.J.,Medical Genetics | Rhead W.,Medical College of Wisconsin | Dimmock D.,Medical College of Wisconsin | And 11 more authors.
Genetics in Medicine

Purpose: Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients. Methods: Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA. Results: In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts. Conclusion: The combination of rituximab with methotrexate intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the nave setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy. © 2012 American College of Medical Genetics. Source

News Article
Site: http://phys.org/biology-news/

Muniswamy Madesh, Ph.D., Professor in the Center for Translational Medicine and the Department of Medical Genetics and Molecular Biochemistry at the Lewis Katz School of Medicine at Temple University. Credit: Lewis Katz School of Medicine at Temple University Inside almost every cell in the human body, tiny mitochondria are continuously generating energy to power countless cellular activities. That process of energy generation also happens to be closely tied to intracellular calcium regulation by a membrane gateway inside mitochondria known as the mitochondrial Ca2+ uniporter (MCU), which has critical roles in both bioenergetics and cell death. How MCU regulates calcium uptake has been unclear, but the recent structural discovery of a key MCU domain by scientists at the Lewis Katz School of Medicine at Temple University points toward the involvement of not one, but two ions - calcium and magnesium - opening new paths to the development of MCU-modulating agents for the treatment of diseases involving mitochondrial dysfunction. "Calcium is a key regulator of energy production in mitochondria, but too much of it can trigger cell death," explained senior investigator on the study, Muniswamy Madesh, PhD, Professor in the Center for Translational Medicine and the Department of Medical Genetics and Molecular Biochemistry at the Lewis Katz School of Medicine (LKSOM) at Temple University. Dr. Madesh and colleagues are the first to solve the crystal structure of the MCU N-terminal domain, which they detail in an article published online August 25, by the journal Cell Chemical Biology. Mitochondrial calcium regulation can set in motion signaling pathways that control cytosolic calcium levels, as well as pathways that influence cell death and energy production and expenditure. Hence, MCU activity is vital to calcium homeostasis and cell survival. "But if the pore fails to close," Dr. Madesh explained, "mitochondria retain the energy they synthesize in the form of ATP. The resulting accumulation of oxidants and calcium overload lead to mitochondrial swelling and cell stress." Such abnormalities in mitochondrial function occur in a variety of diseases, including cardiovascular diseases, such as stroke and heart attack, and certain neurological conditions such as Parkinson's and Alzheimer's diseases. As a result, insight into MCU structure could help researchers find ways to modulate the gateway's activity and potentially restore its function in disease states. In the new study, Dr. Madesh and colleagues describe the atomic structure of the MCU N-terminal domain and report the discovery of a "grasp" region of the domain dedicated specifically to the binding of calcium and magnesium ions. They found that interaction of the ions with the region destabilizes the MCU channel, causing the gateway to close. In experiments in human cells, mutations introduced into the grasp region disrupted MCU assembly and greatly attenuated mitochondrial calcium uptake through the channel. The researchers further discovered that MCU activity could be blocked both by bathing mitochondria in magnesium and by preventing mitochondrial calcium displacement. The discovery supports previous studies, suggesting that MCU is autoregulated via a mechanism involving either calcium-dependent inactivation or magnesium-induced inhibition. According to Dr. Madesh, the new structural and mechanistic insights from his team's study help fill in gaps in scientists' understanding of the role of MCU in controlling mitochondrial calcium uptake. The new findings also have important implications for the understanding of diseases involving mitochondrial dysfunction. "In identifying a region of MCU that directly controls its activity, we have created a framework for modulating MCU function through the development of a small molecule," Dr. Madesh said. Explore further: Researchers identifie gatekeeper protein, new details on cell's power source

Discover hidden collaborations