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Klein Lab - Research

Elucidating the molecular mechanisms of monogenetic immunodeficiencies

Primary immunodeficiency disorders (PIDs) are rare genetic diseases of the immune system, characterized by recurrent infections, autoimmunity, allergy, and cancer. With our dynamic team of clinicians, bioinformaticians and laboratory based biologists, we aim to explore PIDs and identify their underlying genetic cause(s). Through investigation of PIDs, we and other groups have been able to significantly advance our understanding not only of disease but also of the cell biology and biochemistry underpinning the proper functioning of the immune system.

A key step in understanding PIDs is whole genome sequencing (WGS) of patients genomic DNA that, through comparison to publically available reference genomes and healthy relative controls, is analyzed in a manner optimized to specifically identify rare candidate genetic variants, potentially causative of disease. However, given the significant genetic variability within individuals, such an analysis typically generates a number of potential gene candidates that must then be further investigated to assess their potential biological relevance and functional consequence(s). This is achieved through state of the art in vitro and in vivo laboratory based studies, specifically tailored for the gene of interest and the patient disease and phenotype. This factor demands from our researchers a substantial level of versatility, presenting them with a unique challenge and opportunity to continually adapt, update and enhance their skills. Ultimately, utilizing our worldwide network of collaborators, we aim to find secondary cases of disease where comparable patients have been identified with similar gene variants. This final step is essential to validate our findings, as it significantly strengthens the connection between the identified gene alteration and disease.

Fundamental to our ongoing success has been the accumulation of patient cohorts, allowing for the identification of genetic variations common to a number of individuals. Two key diseases in which we have patient cohorts available are severe congenital neutropenia (SCN) and very early onset inflammatory bowel disease (VEO-IBD). Using the afore-mentioned approaches and our patient cohorts, we have successfully identified a number of novel genes associated with both diseases, significantly adding to our understanding of these diseases and approaches available for their treatment. Our work now continues to identify new immune pathologies, their underlying genetic and biology, and improvements in the manner in which they are treated.


Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schaffer AA, Gertz EM, Schambach A, Kreipe HH, Pfeifer D, Engelhardt KR, Rezaei N, Grimbacher B, Lohrmann S, Sherkat R, Klein C (2012) The phenotype of human STK4 deficiency. Blood 119: 3450-3457. PubMed

Bahrami E, Witzel M, Racek T, Puchalka J, Hollizeck S, Greif-Kohistani N, Kotlarz D, Horny HP, Feederle R, Schmidt H, Sherkat R, Steinemann D, Gohring G, Schlegelbeger B, Albert MH, Al-Herz W, Klein C (2017) Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations. The Journal of allergy and clinical immunology. PubMed

Kotlarz D, Ziętara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J, Krawitz PM, Robinson PN, Hecht J, Puchałka J, Gertz EM, Schäffer AA, Lawrence MG, Kardava L, Pfeifer D, Baumann U, Pfister E-D, Hanson EP, Schambach A, Jacobs R, Kreipe H, Moir S, Milner JD, Schwille P, Mundlos S, Klein C (2013) Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. The Journal of experimental medicine 210: 433-443. PubMed

Schober T, Magg T, Laschinger M, Rohlfs M, Linhares ND, Puchalka J, Weisser T, Fehlner K, Mautner J, Walz C, Hussein K, Jaeger G, Kammer B, Schmid I, Bahia M, Pena SD, Behrends U, Belohradsky BH, Klein C, Hauck F (2017) A human immunodeficiency syndrome caused by mutations in CARMIL2. Nature communications 8: 14209. PubMed