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Alexej Knaus

 

Alexej Knaus 

Research interest

On all eukaryotic cells a specific glycolipid functions as an anchor to attach proteins to the plasma membrane: The glycosylphosphatidylinositol (GPI) anchor. There are more than 150 proteins that are attached to the cell surface via the GPI anchor. It therefore plays important roles in signal transduction, cell adhesion, antigen presentation and complement regulation. So far 29 genes have been identified in the synthesis and maturation of the GPI anchor, and attachment and transport of GPI anchored proteins (GPI-APs). Defects in the synthesis and maturation pathway of the GPI anchor, which lead to reduction of GPI-APs, are a subclass of congenital disorders of glycosylation (CDG). Disease-causing mutations have been described for 17 of these genes. Among the most common features in GPI biosynthesis defects (GPIBDs) are intellectual disability, epilepsies, and elevated alkaline phosphatase activity. However, the expressivity of the clinical features varies from severe syndromic forms with multiple organ malformations to mild non-syndromic intellectual disability. Yet, the pathophysiological implications of GPI deficiencies that lead to the broad phenotypic spectrum are only poorly understood. The objectives of my study are: 1st functional characterization of pathogenic mutations in genes of the GPI synthesis pathway, 2nd investigation of the underlying pathophysiological mechanism of GPI deficiencies, 3rd correct diagnosis of exome data based on facial gestalt recognition and flow cytometry in cases with suspected GPIBDs. 

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Scientific Vita

since 2018   Postdoc at the Institute for Genomic Statistics and Bioinformatics, University Bonn, Germany

 
2014-2018   Doctoral student at the Institute for Medical Genetics and Human Genetics, Charité Universitätsmedizin Berlin, Germany
                    Working on GPI anchor deficiencies in the lab of Peter Krawitz.
                    Graduate student at the Berlin Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
 
2013-2014   Business development, support, sales and marketing at GeneTalk GmbH
 
2012-2013   Master of Science in Molecular Biotechnology at the University of Barcelona and 
                    Center of Regenerative Medicine in Barcelona  CMR[B] in the Izpisua Belmonte lab, Barcelona, Spain 
 
2007-2012   Bachelor of Science in Molecular Biomedicine at the Rheinische Friedrich-Wilhelms-Universität Bonn, Germany
                    at the Department of Developmental Pathology in the Schorle lab and at the Life&Brain
 

Publications

 


Mutations in PIGU Impair the Function of the GPI Transamidase Complex, Causing Severe Intellectual Disability, Epilepsy, and Brain Anomalies.

Knaus A, Kortüm F, Kleefstra T, Stray-Pedersen A, Đukić D, Murakami Y, Gerstner T, van Bokhoven H, Iqbal Z, Horn D, Kinoshita T, Hempel M, Krawitz PM.

American Journal of Human Genetics. 2019 Jul 25. doi: 10.1016/j.ajhg.2019.06.009. [Epub ahead of print].

 


Mutations in PIGB Cause an Inherited GPI Biosynthesis Defect with an Axonal Neuropathy and Metabolic Abnormality in Severe Cases.

Murakami Y, Nguyen TTM, Baratang N, Raju PK, Knaus A, Ellard S, Jones G, Lace B, Rousseau J, Ajeawung NF, Kamei A, Minase G, Akasaka M, Araya N, Koshimizu E, van den Ende J, Erger F, Altmüller J, Krumina Z, Strautmanis J, Inashkina I, Stavusis J, El-Gharbawy A, Sebastian J, Puri RD, Kulshrestha S, Verma IC, Maier EM, Haack TB, Israni A, Baptista J, Gunning A, Rosenfeld JA, Liu P, Joosten M, Rocha ME, Hashem MO, Aldhalaan HM, Alkuraya FS, Miyatake S, Matsumoto N, Krawitz PM, Rossignol E, Kinoshita T, Campeau PM.

American Journal of Human Genetics. 2019 Jun 25. pii: S0002-9297(19)30206-X. doi: 10.1016/j.ajhg.2019.05.019. [Epub ahead of print]. PMID: 31256876.

 

Biallelic mutations in PIGP cause developmental and epileptic encephalopathy.

Krenn M, Knaus A, Westphal DS Wortmann SB, Polster T, Woermann FG, Karenfort M, Mayatepek E, Meitinger T Wagner M,
Distelmaier F.

Annals of Clinical and Translational Neurology. 2019. Apr 11;6(5):968-973. doi: 10.1002/acn3.768. eCollection 2019 May.
PMID: 31139695

 

PEDIA: prioritization of exome data by image analysis.

Hsieh TC, Mensah MA Pantel JT, Aguilar D, Bar O, Bayat A, Becerra-Solano L, Bentzen HB, Biskup S, Borisov O, Braaten O, Ciaccio C, Coutelier M, Cremer K, Danyel M, Daschkey S, Eden HD, Devriendt K, Wilson S, Douzgou S Đukić D, Ehmke N, Fauth C, Fischer-Zirnsak B, Fleischer N, Gabriel H, Graul-Neumann L, Gripp KW, Gurovich Y, Gusina A, Haddad N, Hajjir N, Hanani Y, Hertzberg J, Hoertnagel K, Howell J, Ivanovski I, Kaindl A, Kamphans T, Kamphausen S, Karimov C, Kathom H, Keryan A, Knaus A, Köhler S, Kornak U, Lavrov A, Leitheiser M, Lyon GJ, Mangold E, Reina PM, Carrascal AM, Mitter D, Herrador LM, Nadav G, Nöthen M, Orrico A, Ott CE, Park K, Peterlin B, Pölsler L, Raas-Rothschild A, Randolph L, Revencu N, Fagerberg CR, Robinson PN, Rosnev S, Rudnik S, Rudolf G, Schatz U, Schossig A, Schubach M, Shanoon O, Sheridan E, Smirin-Yosef P, Spielmann M, Suk EK, Sznajer Y, Thiel CT, Thiel G, Verloes A, Vrecar I, Wahl D, Weber I, Winter K, Wiśniewska M, Wollnik B, Yeung MW, Zhao M, Zhu N, Zschocke J, Mundlos S, Horn D, Krawitz PM.

Genetics in Medicine. 2019. Jun 5. doi: 10.1038/s41436-019-0566-2. [Epub ahead of print]. PMID: 31164752

  

PIGT-CDG, a disorder of the glycosylphosphatidylinositol anchor: description of 13 novel patients and expansion of the clinical characteristics.

Bayat A, Knaus A, Juul AW, Dukic D, Gardella E, Charzewska A, Clement E, Hjalgrim H,, Hoffman-Zacharska D, Horn D, Horton R, Hurst JA, Josifova D, Larsen LHG, Lascelles K, Obersztyn E, Pagnamenta A, Pal DK, Pendziwiat M, Ryten M, Taylor J, Vogt J, Weber Y, DDD Study Group, Krawitz PM, Helbig I, Kini U, Møller RS.

Genetics in Medicine. 2019. Apr 12. doi:10.1038/s41436-019-0512-3. [Epub ahead of print]. PMID: 30976099

 

Familial Xp11.22 microdeletion including SHROOM4 and CLCN5 is associated with intellectual disability, short stature, microcephaly and Dent disease: a case report.

Danyel M, Suk EK, Raile V, Gellermann J, Knaus A, Horn D.

BMC Medical Genomics. 2019. Jan 10;12(1):6. doi: 10.1186/s12920-018-0471-6. PMID: 30630535

  

Multisite de novo mutations in human offspring after paternal exposure to ionizing radiation.

Holtgrewe M, Knaus A, Hildebrand G, Pantel JT, Santos MRL, Neveling K, Goldmann J, Schubach M, Jäger M, Coutelier M, Mundlos S, Beule D, Sperling K, Krawitz PM.

Scientific Reports. 2018 Oct 2;8(1):14611. doi: 10.1038/s41598-018-33066-x.. PMID: 30279461

 

Characterization of glycosylphosphatidylinositol biosynthesis defects by clinical features, flow cytometry, and automated image analysis.

Knaus A, Pantel JT, Pendziwiat M, Hajjir N, Zhao M, Hsieh TC, Schubach M, Gurovich Y, Fleischer N, Jäger M, Köhler S, Muhle H, Korff C, Møller RS, Bayat A, Calvas P, Chassaing N, Warren H, Skinner S, Louie R, Evers C, Bohn M, Christen HJ, van den Born M, Obersztyn E, Charzewska A, Endziniene M, Kortüm F, Brown N, Robinson PN, Schelhaas HJ, Weber Y, Helbig I, Mundlos S, Horn D, Krawitz PM.

Genome Medicine. 2018 Jan 9;10(1):3. doi: 10.1186/s13073-017-0510-5. PMID: 29310717

 

A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia.

Türkmen S, Spielmann M, Güneş N, Knaus A, Flöttmann R, Mundlos S, Tüysüz B.

Molecular Syndromology. 2017 Nov;8(6):318-324. doi: 10.1159/000479721. Epub 2017 Sep 8. PMID: 29230162

 

Reduced cell surface levels of GPI-linked markers in a new case with PIGG loss of function.

Zhao JJ, Halvardson J, Knaus A, Georgii-Hemming P, Baeck P, Krawitz PM, Thuresson AC, Feuk L.

Human Mutation 2017 Oct;38(10):1394-1401. doi: 10.1002/humu.23268. Epub 2017 Jun 12. PMID: 28581210

 

Rare Noncoding Mutations Extend the Mutational Spectrum in the PGAP3 Subtype of Hyperphosphatasia with Mental Retardation Syndrome.

Knaus A, Awaya T, Helbig I, Afawi Z, Pendziwiat M, Abu-Rachma J, Thompson MD, Cole DE, Skinner S, Annese F, Canham N, Schweiger MR, Robinson PN, Mundlos S, Kinoshita T, Munnich A, Murakami Y, Horn D, Krawitz PM.

Human Mutation 2016 Aug;37(8):737-44. doi: 10.1002/humu.23006. Epub 2016 May 19. PMID: 27120253

 

A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation.

Ibrahim DM, Tayebi N, Knaus A, Stiege AC, Sahebzamani A, Hecht J, Mundlos S, Spielmann M.

American Journal of Mededical Genetics A. 2016 Mar;170(3):615-21. doi: 10.1002/ajmg.a.37464. Epub 2015 Nov 18. PMID: 26581570

 

Crowdsourced direct-to-consumer genomic analysis of a family quartet.

Corpas M, Valdivia-Granda W, Torres N, Greshake B, Coletta A, Knaus A, Harrison AP, Cariaso M, Moran F, Nielsen F, Swan D, Weiss Solís DY, Krawitz P, Schacherer F, Schols P, Yang H, Borry P, Glusman G, Robinson PN.

BMC Genomics. 2015 Nov 7;16:910. doi: 10.1186/s12864-015-1973-7. PMID: 26547235

 

FGFR2 mutation in a patient without typical features of Pfeiffer syndrome--The emerging role of combined NGS and phenotype based strategies.

Flöttmann R, Knaus A, Zemojtel T, Robinson PN, Mundlos S, Horn D, Spielmann M.

European Journal of Mededical Genetics. 2015 Aug;58(8):376-80. doi: 10.1016/j.ejmg.2015.05.007. Epub 2015 Jun 19. 
PMID: 26096994

 

Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome.

Ehmke N, Caliebe A, Koenig R, Kant SG, Stark Z, Cormier-Daire V, Wieczorek D, Gillessen-Kaesbach G, Hoff K, Kawalia A, Thiele H, Altmüller J, Fischer-Zirnsak B, Knaus A, Zhu N, Heinrich V, Huber C, Harabula I, Spielmann M, Horn D, Kornak U, Hecht J, Krawitz PM, Nürnberg P, Siebert R, Manzke H, Mundlos S.

American Journal of Mededical Genetics A. 2014 Dec 4;95(6):763-70. doi: 10.1016/j.ajhg.2014.11.004. PMID: 25480037

 

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