Neurogenetics

Research Group

"Our goal is to elucidate the causes and pathomechanisms of rare brain malformations. In particular, we focus on the genetics of syndromic intellectual development disorders, complex brain malformations and cytoskeletal actinopathies. By uncovering the pathomechanisms of the diseases, we pave the way for improved treatment strategies in concordance with the complexity of human biology."

Prof. Dr. med. Nataliya Di Donato

Group leader, Director Department for Human Genetics

Curriculum Vitae | Contact | ORCID


Research Goal

By using the latest NGS/high-throughput sequencing methods, we identify genetic regions and new genes that are involved in embryonic brain development and lead to malformations when mutated. Animal models, advanced brain organoids as well as human cellular systems help us to gain further insights into the effects of these mutations. To dissect the function of the relevant genetic domains we are using modern biochemical and biophysical methods to understand the the role in central pathways in neuronal development and above.

Focus of Research

Chemicals sortiment in the lab. Picture from Freepik on Freepik.

Actinopathies

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Brain Study. Picture by rawpixel.com on Freepik

Rare Neurological Disorders

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Doctor looking at CT scan. Picture from Freepik on Freepik

Brain Malformations

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Actinopathies

Focus of Resarch

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a genetic disorder caused by a mutation in either the ACTB or ACTG1 gene. There are currently around 100 affected people diagnosed worldwide. This disease is now being recognized more and more frequently. Patients are often born with one or more malformations, show delayed motor and mental development and can develop seizures and neuropathy (for detailed information, see Baraitser-Winter Cerebrofrontofacial Syndrome).

The ACTB and ACTG1 genes encode two similar proteins - beta-actin and gamma-actin, which are two main components of the cytoskeleton (cell scaffolding). The change in protein structure leads to developmental disorders of several organs and, in particular, to maldevelopment of the cerebral cortex.  

In cooperation with other human genetic institutions, we aim to create a patient register and a biobank specific for non-muscular actinopathies (NMA). This will lay the foundation for further research into the disease mechanisms. The systematic collection of relevant clinical information will allow us to analyze the course of the disease and develop precise treatment recommendations.

The European consortium PredACTINg, which is coordinated by us, is also investigating the pathomechanisms that lead to BWCFF and other non-muscular actinopathies using a variety of sophisticated methods. Further information on the consortium can be found here.

Selected Publications:

Variants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia. Latham SL, Ehmke N, Reinke PYA, Taft MH, Eicke D, Reindl T, Stenzel W, Lyons MJ, Friez MJ, Lee JA, Hecker R, Frühwald MC, Becker K, Neuhann TM, Horn D, Schrock E, Niehaus I, Sarnow K, Grützmann K, Gawehn L, Klink B, Rump A, Chaponnier C, Figueiredo C, Knöfler R, Manstein DJ, Di Donato N. Nat Commun. 2018 Oct 12;9(1):4250. doi: 10.1038/s41467-018-06713-0.

Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome.  Di Donato N, Kuechler A, Vergano S, Heinritz W, Bodurtha J, Merchant SR, Breningstall G, Ladda R, Sell S, Altmüller J, Bögershausen N, Timms AE, Hackmann K, Schrock E, Collins S, Olds C, Rump A, Dobyns WB.Am J Med Genet A. 2016 Oct;170(10):2644-51. doi: 10.1002/ajmg.a.37771. Epub 2016 May 30.PMID: 27240540

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases. Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenço CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Rivière JB, Dobyns WB, Pilz DT.  Eur J Hum Genet. 2015 Mar;23(3):292-301. PMID: 25052316, doi: 10.1038/ejhg.2014.95

Baraitser-Winter cerebrofrontofacial syndrome: delineation of the spectrum in 42 cases.  Verloes A, Di Donato N, Masliah-Planchon J, Jongmans M, Abdul-Raman OA, Albrecht B, Allanson J, Brunner H, Bertola D, Chassaing N, David A, Devriendt K, Eftekhari P, Drouin-Garraud V, Faravelli F, Faivre L, Giuliano F, Guion Almeida L, Juncos J, Kempers M, Eker HK, Lacombe D, Lin A, Mancini G, Melis D, Lourenço CM, Siu VM, Morin G, Nezarati M, Nowaczyk MJ, Ramer JC, Osimani S, Philip N, Pierpont ME, Procaccio V, Roseli ZS, Rossi M, Rusu C, Sznajer Y, Templin L, Uliana V, Klaus M, Van Bon B, Van Ravenswaaij C, Wainer B, Fry AE, Rump A, Hoischen A, Drunat S, Rivière JB, Dobyns WB, Pilz DT.Eur J Hum Genet. 2015 Mar;23(3):292-301. doi: 10.1038/ejhg.2014.95. Epub 2014 Jul 23.

Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. Di Donato N, Rump A, Koenig R, Der Kaloustian VM, Halal F, Sonntag K, Krause C, Hackmann K, Hahn G, Schrock E, Verloes A.Eur J Hum Genet. 2014 Feb;22(2):179-83. doi: 10.1038/ejhg.2013.130. Epub 2013 Jun 12.PMID: 23756437

 

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Rare neurological disorders

Focus of Research

Project I: Reelinopathies

The cerebral cortex of the human brain - the cortex - is characterized by a characteristic and very complex layering of different nerve cells. This typical brain structure is formed during embryonic development through the strictly regulated migration of nerve cells, in which the protein reelin (RELN) is significantly involved. Impairments of the RELN signaling pathway lead to abnormal cortical layer formation, which affects neuronal plasticity and connectivity in the adult brain. Thus, disorders in RELN signaling are associated with a broad spectrum of developmental neurological and psychiatric disorders. The clinical spectrum of RELN-associated disorders is very broad and includes schizophrenia, autism and bipolar disorders. The exact mechanisms of this clinical variability are still unclear. Various mutations in the DNA sequence coding for the RELN have already been correlated with a clinically conspicuous phenotype. To elucidate the pathophysiological mechanisms of patient-specific RELN mutations, we use cell culture models, including 3D culture of cortical organoids, to model the disease in vitro. The aim is to mimic the effect of RELN alterations on neuronal migration in an in vitro culture model to gain new insights into the function of reelin during early embryonic development and the physiological function of the reelin protein in relation to human neurogenesis.

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Selected publications:

Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders. Di Donato N, Guerrini R, Billington CJ, Barkovich AJ, Dinkel P, Freri E, Heide M, Gershon ES, Gertler TS, Hopkin RJ, Jacob S, Keedy SK, Kooshavar D, Lockhart PJ, Lohmann DR, Mahmoud IG, Parrini E, Schrock E, Severi G, Timms AE, Webster RI, Willis MJH, Zaki MS, Gleeson JG, Leventer RJ, Dobyns WB. Brain. 2022 Sep 14;145(9):3274-3287. doi: 10.1093/brain/awac164. PMID: 35769015 Free PMC article.

Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Di Donato N, Timms AE, Aldinger KA, Mirzaa GM, Bennett JT, Collins S, Olds C, Mei D, Chiari S, Carvill G, Myers CT, Rivière JB, Zaki MS; University of Washington Center for Mendelian Genomics; Gleeson JG, Rump A, Conti V, Parrini E, Ross ME, Ledbetter DH, Guerrini R, Dobyns WB. Genet Med. 2018 Nov;20(11):1354-1364. doi: 10.1038/gim.2018.8. Epub 2018 Apr 19. PMID: 29671837 Free PMC article.

 

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Brainmalformations

Focus of Research

Brightfield image of neuronal organoid. Picture by Indra Niehaus / MHH

Project I: Organoid-based modeling of cerebral malformations

We are interested in the development of the human brain and the development of genetic brain malformations. To model the diseases, we use miniature organ-mimicking, three-dimensional cell constructs, so-called cerebral organoids, for our research. We generate these from induced pluripotent stem cells that have been reprogrammed from the patient's own fibroblasts from a skin biopsy. Our aim is to elucidate the molecular and pathophysiological mechanisms of brain malformations.

Collaborations:

This project is carried out in close collaboration with Dr. Michael Heide (AG Huttner at the MPI-CBG, Dresden).

Funding:

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Project II: Genetics of cortical malformations

Malformations of the cerebral cortex (cortical malformation, malformation of cortical development) are heterogeneous and represent an important cause of mental development disorders and epilepsy. They differ in their aetiology, mechanism of development, morphology, course and prognosis.
We are involved in the classification and elucidation of genetic causes of lissencephaly as well as other neuronal migration disorders (e.g. periventricular heterotopias) and disorders of cortical organization (e.g. polymicrogyria). Each patient first receives a detailed clinical assessment, including dysmorphologic evaluation of clinical photographs and a cranial MRI. If a genetic cause comes into question, we use high-throughput sequencing to identify the responsible changes. Close collaboration with several leading research groups in the field allows us to successfully identify new disease genes. This procedure goes far beyond routine genetic diagnostics.
Participation in the study is voluntary and free of charge. We process every request and provide an assessment of the MRI images as well as recommendations for further diagnostics.

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Team

  • Dr. Indra Niehaus
  • Samira Zarvandi, M.Sc.