New genetic causes of Bloom syndrome identified

Mutations causing Bloom syndrome have been identified in two new genes by an international collaboration of scientists including also researchers of the Institute of Human Genetics Göttingen. Bloom syndrome is a rare congenital disorder characterized by primary microcephaly, growth retardation, skin affections and intellectual disability. Patients with Bloom syndrome are also predisposed to the development of cancer, with a mean age of onset in the third decade of life.

The researchers in Göttingen investigated a Turkish family with two cousins who manifested developmental delay, mild intellectual disability, pronounced primary microcephaly and short stature and were clinically diagnosed with a Bloom syndrome-like disorder. Exome sequencing identified in both affected individuals a homozygous 5-bp deletion in RMI1 as the underlying cause of the condition. The protein encoded by RMI1 is a member of the BRT protein complex – just like TOP3A, in which their collaboration partners in this study detected novel causative variants in 10 other patients with Bloom syndrome. The BTR complex plays an essential role in homologous recombination, an important mechanism in the repair of DNA damage. Homozygous mutations in BLM, another BTR component, have previously been described as causing Bloom syndrome.

The results of the study have been published in the American Journal of Human Genetics.

Martin C-A, Sarlós K, Logan CV, Thakur RS, Parry DA, Bizard AH, Leitch A, Cleal L, Ali NS, Al-Owain MA, Allen W, Altmüller J, Aza-Carmona M, Barakat BAY, Barraza-García J, Begtrup A, Bogliolo M, Cho MT, Cruz-Rojo J, Dhahrabi HAM, Elcioglu NH, GOSgene, Gorman GS, Jobling R, Kesterton I, Kishita Y, Kohda M, Le Quesne Stabej P, Malallah AJ, Nürnberg P, Ohtake A, Okazaki Y, Pujol R, Ramirez MJ, Revah-Politi A, Shimura M, Stevens P, Taylor RW, Turner L, Williams H, Wilson C, Yigit G, Zahavich L, Alkuraya FS, Surralles J, Iglesais A, Murayama K, Wollnik B, Dattani M, Heath KE, Hickson ID, Jackson AP. Mutations in TOP3A Cause a Bloom Syndrome-like Disorder. Am J Hum Genet. 2018;103(2):221-231. doi:10.1016/j.ajhg.2018.07.001.

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An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis

During translation, a number of obstacles have the potential to arrest the ribosomal movement. In yeast, several studies revealed that the evolutionarily conserved Pelota (Pelo) recognizes stalled ribosomes and dissociates ribosomal subunits. In mammals, little is known about the role of Pelo in the ribosome-rescue machinery. An international collaboration with the participation of Prof. Ibrahim Adham at the Institute of Human Genetics Göttingen has studied conditional mouse lines in which Pelo is deleted in different epidermal stem cell lineages. They found that loss of the ribosome-rescue factor Pelo in specific epidermal stem cell lineage results in hyperproliferation and altered differentiation of these cells. By contrast, deletion of Pelo in other epidermal stem cell lineages has no effect or induces a mild phenotype. Further molecular analyses demonstrated that the Pelo deletion results in global upregulation of translation, rather than affecting the expression of specific genes. These results reveal that the ribosome-rescue machinery is essential for mammalian tissue homeostasis.

The results of the study have been published in Nature.

Liakath-Ali K, Mills EW, Sequeira I, Lichtenberger BM, Pisco AO, Sipilä KH, Mishra A, Yoshikawa H, Wu CC, Ly T, Lamond AI, Adham IM, Green R, Watt FM. An evolutionarily conserved ribosome-rescue pathway maintains epidermal homeostasis. Nature. 2018 Apr;556(7701):376-380. doi: 10.1038/s41586-018-0032-3. Epub 2018 Apr 11.

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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 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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