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Brittle bone disease: Novel gene provides clue to potential therapeutic approach in the future

Extremely fragile bones are the reason why mainly children, but also adults with brittle bone disease will frequently break their bones, often even without any apparent injury. The genetic disease, also called osteogenesis imperfecta (OI), may present in varying forms from mild to severe and can also be associated with other symptoms including short height, hearing loss, skeletal deformity, loose joints, impaired vision and others. OI is a rare disease and affects 4 to 7 in 100.000 people. So far, a number of genes have been described in which defects might lead to disturbed bone formation and to the development of OI. Nevertheless, in some patients the underlying genetic cause remains unclear.

Led by the research group of Bernd Wollnik, Director of the Institute of Human Genetics at the University Medical Center Göttingen (UMG), a collaboration of scientists from Germany, Brazil, Portugal, UK and Switzerland has now discovered a novel gene involved in the development of OI. They studied five patients with progressive skeletal deformities who had suffered multiple bone fractures before their second year of life or even before birth, and they identified mutations in a novel gene: MESD. “We performed whole-exome sequencing in all patients, which means, we analyzed all coding regions of all 19.000 genes of the human genome in parallel. Before doing so, we had checked whether the patients carried any potentially disease-causing variations in genes that we already know to be connected with OI. They did not – but instead we discovered that they all had a mutation in both copies of the MESD gene. MESD has never before been linked to a human disorder, but we knew that it is involved in the WNT signaling pathway. This made it an excellent candidate for us”, describes Bernd Wollnik.

The WNT signaling pathway is a major network of various molecules and regulates fundamental cellular processes including embryonic development, cell differentiation and cell division. Although MESD is not a direct component of the WNT pathway, it acts indirectly within this network. As a chaperone protein it ensures that specific WNT receptor molecules, LRP5 and LRP6, adopt the protein folding they need for their correct functioning and that they traffic from the endoplasmatic reticulum to the cell membrane.

The researchers also performed detailed experiments in different animal models to elucidate the functional consequences of the identified mutation in cells. They showed that, due to their specific position in the protein, the mutations led to a reduction of MESD function but not to a complete loss. The role of WNT signaling in bone growth and strength had already been known. The Wollnik research group had in a previous study several years ago also demonstrated that a protein called WNT1, another component in this pathway, is relevant for bone formation and bone cell function.

So far there is no cure for OI. Therapy is based on surgery, physical therapy and medical treatment with bisphosphonates. However, in the current study, the use of bisphosphonates did not produce any positive effect. For Bernd Wollnik, this study also opens new perspectives for the treatment of OI: “Our cell experiments hint to a novel approach: Biological agents activating WNT signaling might be a potential treatment option for patients with MSED-associated OI.” Such a drug is already available and used to treat patients with aging-associated osteoporosis to increase bone formation and bone mass.

Bernd Wollnik and his research group at the Institute of Human Genetics in Göttingen have been intensively working on elucidating the genetic causes and molecular mechanisms of rare diseases. Their research focuses especially on disorders with premature aging (progeroid diseases), microcephalies and the biological processes underlying genomic instability.

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

Autosomal Recessive Mutations in MESD Cause Osteogenesis Imperfecta.
Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, Valadares ER, de Sousa SB, Maia S, Saraiva J, Honjo RS, Kim CA, Cabral de Menezes H, Lausch E, Lorini PV, Lamounier A Jr, Carniero TCB, Giunta C, Rohrbach M, Janner M, Semler O, Beleggia F, Li Y, Yigit G, Reintjes N, Altmüller J, Nürnberg P, Cavalcanti DP, Zabel B, Warman ML, Bertola DR, Wollnik B, Netzer C.
Am J Hum Genet. 2019 Sep 20. pii: S0002-9297(19)30312-X. doi: 10.1016/j.ajhg.2019.08.008. [Epub ahead of print]

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NIG: Modern integrated genomics is a key element to innovative research and personalized medicine

Genomics, epigenomics and transcriptomics are crucial elements in modern biomedical research towards personalized medicine. Next-generation sequencing, the technology that allows to simultaneously analyze millions of DNA or RNA molecules, is a powerful tool that opens new research horizons. NIG, the NGS Core Unit for Integrated Genomics at the University Medical Center Göttingen (UMG), is an internationally recognized service provider that delivers a broad portfolio of the latest technologies and methods to research groups and offers its users flexible and cost-efficient NGS applications within modern research approaches.

“Here at NIG, we have the longstanding expertise, first-rate technical equipment and refined infrastructure needed to successfully realize research projects. Our users benefit from a comprehensive service ranging from project design and selection of suitable methods to performing a broad range of state-of-the-art NGS-based experiments. In addition, we can also provide extensive statistical and bioinformatics support throughout the process, from assisting with experimental design to analyzing the generated experimental data” explains Dr. Gabriela Salinas, Head of NIG.

Prof Bernd Wollnik, Director of the Institute of Human Genetics, to which NIG is functionally affiliated, sees NIG as a key element and driver within UMG’s research structure: “This core unit delivers high-quality NGS data to researchers who analyze them by means of complex algorithms and bioinformatics pipelines to extract important insights into the processes that take place in specific biological systems, signaling pathways and organs. These methods and findings are central to the progress of personalized medicine.”

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Hallermann-Streiff syndrome: The molecular link of the well-known syndrome is still missing

Hallermann-Streiff syndrome is a rare congenital syndrome that is well-known but whose genetic cause has so far not been unraveled – although researchers have intensively investigated the disorder, using the latest applications of high-throughput sequencing, which have considerably facilitated the identification of disease-associated genes in recent years. Clinically, it presents as a combination of craniofacial dysmorphism, eye malformations, hair and skin anomalies, short stature, and, especially, a characteristic face that usually leads to the clinical diagnosis. Interestingly, affected children may also show signs of accelerated aging. Hallermann-Streiff syndrome thus belongs to the group of so called progeroid syndromes. In a review article published in the American Journal of Medical Genetics, researchers of the Institute of Human Genetics Göttingen summarize the current knowledge on the clinical characteristics of the syndrome and discuss the missing molecular link. Furthermore, they present innovative strategies that may be applied to identify the genetic basis of Hallermann-Streiff syndrome in the future.

Hallermann-Streiff syndrome: A missing molecular link for a highly recognizable syndrome.
Schmidt J, Wollnik B.
Am J Med Genet C Semin Med Genet. 2018 Dec;178(4):398-406. doi: 10.1002/ajmg.c.31668. Review.

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Rapid aging: Biallelic POLR3A mutations cause neonatal progeroid syndrome

An international collaboration of scientists including researchers of the Institute of Human Genetics Göttingen have determined specific mutations in POLR3A as the genetic cause of Wiedemann-Rautenstrauch syndrome. This rare disorder is associated with signs of accelerated aging; it is thus a so called progeroid syndrome. Affected children show characteristic features like growth retardation, sparse scalp hair, lipodystrophy and an unusual face already at birth. They appear to be prematurely aged.

POLR3A, the protein encoded by the gene, forms the largest subunit of the RNA polymerase III complex. This enzyme is crucially involved in the synthesis of RNA in transcription. Specifically, RNA polymerase III transcribes small RNAs including ribosomal RNA (rRNA) and transfer RNA (tRNA). In their study recently published in the Journal of Medical Genetics, the researchers discovered biallelic POLR3A mutations in eight affected families. The types of the identified mutations suggest that specific combinations of compound heterozygous variants of POLR3A must be present to cause the phenotype, including one variant that has a strong detrimental effect on protein function (splice-site or truncating mutation) and a variant exerting a milder functional effect (often an intronic variant).

Progeroid syndromes are a clinically heterogeneous family of disorders which share the feature of premature aging. Various genetic defects have so far been identified as molecular causes, affecting fundamental processes like chromatin structure, genome stability, transcription control, DNA repair, nuclear structure and epigenetic regulation. Researchers at the UMG Institute of Human Genetics are intensively investigating this group of disorders. Their work within this study has been funded by CRC 1002 (“Modulatory units in heart failure”; speaker Prof. Dr. Gerd Hasenfuß). The Institute has also established a special clinic for families with progeroid syndromes.

Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome
Paolacci S, Li Y, Agolini E, Bellacchio E, Arboleda-Bustos CE, Carrero D, Bertola D, Al-Gazali L, Alders M, Altmüller J, Arboleda G, Beleggia F, Bruselles A, Ciolfi A, Gillessen-Kaesbach G, Krieg T, Mohammed S, Müller C, Novelli A, Ortega J, Sandoval A, Velasco G, Yigit G, Arboleda H, Lopez-Otin C, Wollnik B*, Tartaglia M*, Hennekam RC* (*contributed equally).
J Med Genet. 2018 Oct 15; Epub ahead of print

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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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