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Molecular Biology of Hearing and Deafness conference 2018, May 16-19, 2018, in Göttingen

The 11th Molecular Biology of Hearing and Deafness Conference will be held from May 16th to 19th, 2018, at the Max Planck Institute of Biophysical Chemistry in Göttingen. This international conference serves the exchange of researchers about the latest developments in the field. Here, besides the identification of so-far unknown deafness genes, new methods of exome/genome analysis will be presented. Advances in the identification of gene-function relationships will be discussed as well as the role of specific genes in the molecular physiology of hearing and in age-dependent hearing loss. Speakers will also cover potential strategies for gene therapy and prepare the transfer of the results from basic research into clinical application.

More details can be found at www.mbhd2018.de. Registration will be open until March 31st.

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Progeroid malformation syndrome caused by SLC25A24 mutations

An international group of researchers have revealed de novo mutations in SLC25A24 as the genetic cause of Gorlin-Chaudry-Moss syndrome (GCMS) in five affected children. This congenital disease manifests as a combination of malformations of the head and face, short stature, hair anomalies, small eyes, and shortened fingers/toes. Reduced subcutaneous fat and loose skin give some patients a progeroid appearance. To date, only a few affected individuals have been described worldwide. Researchers at the Institute of Human Genetics Göttingen have contributed to the elucidation of the genetic cause of this extremely rare disease: Using exome sequencing, they uncovered a disease-associated variant of SLC25A24 in their patient, a girl who had initially been diagnosed with a suspected neonatal progeroid syndrome. Their work has been funded by SFB1002.

SLC25A24 encodes a protein of the mitochondrial inner membrane. Interestingly, the identified mutations in all five children of the study affect the same amino acid of the SLC25A24 protein, which suggests a specific pathogenic mechanism. Functional investigations performed by the researchers in this study showed that the mutations cause mitochondrial dysfunction and that mutated cells are more susceptible to oxidative stress in vitro. The results, which have now been published in the American Journal of Human Genetics, suggest that the signs of premature aging in the patients are due to a disturbed development of skeletal, fat and connective tissue caused by dysfunction of the mitochondrial membrane transporter.

De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.
Ehmke N, Graul-Neumann L, Smorag L, Koenig R, Segebrecht L, Magoulas P, Scaglia F, Kilic E, Hennig AF, Adolphs N, Saha N, Fauler B, Kalscheuer VM, Hennig F, Altmüller J, Netzer C, Thiele H, Nürnberg P, Yigit G, Jäger M, Hecht J, Krüger U, Mielke T, Krawitz PM, Horn D, Schuelke M, Mundlos S, Bacino CA, Bonnen PE, Wollnik B, Fischer-Zirnsak B, Kornak U.
Am J Hum Genet. 2017 Nov 2;101(5):833-843. doi: 10.1016/j.ajhg.2017.09.016.

 

 

Progeroid syndromes are a key research area of the Wollnik Group at the Institute of Human Genetics. The Institute also runs a specialized Center for Progeroid Syndromes together with the Children’s Hospital as part of the Center of Rare Diseases Göttingen (ZSEG). It unites research and diagnostics related to this rare group of diseases and provides interdisciplinary care to patients with progeroid syndromes.

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CDK10 mutations cause new syndrome of growth retardation, facial dysmorphism, developmental delay and spine malformations

Autosomal recessive mutations of the CDK10 gene have been revealed as causing a newly described syndrome characterized by a combination of severe growth retardation, dysmorphic facial features, spine malformation and developmental delay. CDK10 belongs to the group of CDK protein kinases, which play important roles in cell cycle control, transcription and development, and it has been known to form a complex with cyclin M to phosphorylate substrates such as the transcription factor ETS2 and the protein kinase PKN2. The authors of the study recently published in the American Journal of Human Genetics performed comprehensive functional investigations including a knockout mouse model. They confirmed the human phenotype and the pathogenicity of the CDK10 mutations identified in their patients and uncovered important details on the molecular etiology.

The nine patients originated from five families and were initially studied by separate research groups including a team at the Institute of Human Genetics Göttingen. They were all identified as carrying homozygous loss-of-function mutations in CDK10. The researchers then used the online tool GeneMatcher to connect and to establish an international collaboration to report on this new syndrome.

CDK10 mutations in humans and mice cause severe growth retardation, spine malformations, and developmental delays
Windpassinger C, Piard J, Bonnard, C, … Al Kaissi A, Reversade B, Kaldis P.
Am J Hum Genet. 2017 Sep 7;101(3):391-403. doi: 10.1016/j.ajhg.2017.08.003.

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Novel potential strategy to enhance the efficacy of colorectal carcinoma treatment uncovered

Researchers led by Dr Silke Kaulfuß at the Institute of Human Genetics Göttingen have uncovered a new approach that may increase the efficacy of the standard therapy to treat colorectal cancer (CRC). CRC is one of the most common cancers worldwide and is treated by various combinations of surgery, radiation and chemotherapy. Innovative therapeutic approaches also use substances that selectively target tumor-specific features in order to inhibit the growth of tumor cells.

In their experiments in cell cultures and a mouse model, the researchers used small molecule inhibitors specifically blocking two receptor tyrosine kinases, insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR), and evaluated their effect when they are simultaneously applied in addition to radiation and chemotherapy. These investigations showed that combined inhibition of IGF1R and EGFR in vitro resulted in a stronger reduction of downstream signaling, impairment of DNA repair and induction of apoptosis in tumor cells. This suggests a promising new strategy to treat CRC that might be used in addition to radiochemotherapy.

The results of the study have been published in Cancer Letters.

Simultaneous inhibition of IGF1R and EGFR enhances the efficacy of standard treatment for colorectal cancer by the impairment of DNA repair and the induction of cell death
Oberthür R, Seemann H, Gehrig J, Rave-Fränk M, Bremmer F, Halpape R, Conradi LC, Scharf JG, Burfeind P, Kaulfuß S.
Cancer Lett. 2017 Aug 18;407:93-105. doi: 10.1016/j.canlet.2017.08.009. [Epub ahead of print]

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UMG researchers are unravelling important functional aspects of “broken-heart syndrome”

It is an acute and life-threatening functional disturbance of the heart with symptoms similar to a heart attack, and it really is not so rare: Takotsubo syndrome (TTS) is also called “broken-heart syndrome” because it can also occur when a person experiences intense physical or emotional stress such as the loss or death of a loved one.

The underlying mechanism of this disease is still unknown, but scientists assume that a beta-adrenergic-mediated impairment of cardiac muscle cell function may be implicated in its etiology and that also a genetic predisposition may be involved. At the Heart Center Göttingen, researchers led by Dr Katrin Streckfuss-Bömeke are intensely working on elucidating the pathogenic mechanisms of this syndrome. In their study, they reprogrammed somatic cells of patients with TTS to induced pluripotent stem cells, which were then differentiated into cardiomyocytes. The researchers then treated these cells with catecholamines, thereby simulating an excessive release of stress hormones in the patient. They found that in the cell model similar molecular reactions occurred as in TTS patients, as for example beta-adrenergic signaling was enhanced. This cell model thus allows to investigate in detail the molecular and cellular processes in cardiomyocytes in order to unravel the pathomechanisms of the broken-heart syndrome. In addition to the functional investigations, genetic analyses were performed in close cooperation with the Institute of Human Genetics to shed light on the genetic background of the disease.

The results of the functional and initial genetic analyses of this study have been published in the Journal of the American College of Cardiology.

Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
Borchert T, Hübscher D, Guessoum CI, Lam TD, Ghadri JR, Schellinger IN, Tiburcy M, Liaw NY, Li Y, Haas J, Sossalla S, Huber MA, Cyganek L, Jacobshagen C, Dressel R, Raaz U, Nikolaev VO, Guan K, Thiele H, Meder B, Wollnik B, Zimmermann WH, Lüscher TF, Hasenfuss G, Templin C, Streckfuss-Bömeke K
J Am Coll Cardiol. 2017 Aug 22;70(8):975-991. doi: 10.1016/j.jacc.2017.06.061.

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