Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations

Bahrami, Ehsan; Witzel, Maximilian; Raček, Tomáš; Puchałka, Jacek; Hollizeck, Sebastian; Greif-Kohistani, Naschla; Kotlarz, Daniel; Horny, Hans‐Peter; Feederle, Regina; Schmidt, Heinrich; Sherkat, Roya; Steinemann, Doris; Göhring, Gudrun; Schlegelbeger, Brigitte; Albert, Michael H.; Al‐Herz, Waleed; Klein, Christoph

doi:10.1016/j.jaci.2016.10.053

Cited by 44 publications

(64 citation statements)

References 33 publications

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“…Given the functional interaction of Mysm1 with the p19 Arf ‐p53 axis in certain tumors (36), future studies may address osteosarcoma occurrence in Mysm1 ‐/‐ p53 ‐/‐ DKO mice. Interestingly, some of the phenotypic anomalies caused by Mysm1 deficiency in mice were also found in humans with mutations in MYSM1 (37, 38), underlining the clinical relevance of the interaction of Mysm1 with tumor‐suppressor genes. Although we could not detect any significant differences in growth‐plate architecture and width in MKO and DKO relative to WT mice in our current analyses, an additional effect of Mysm1 deficiency on chondrocytes cannot be fully excluded at this point.…”

Section: Discussionmentioning

confidence: 98%

Loss of p53 compensates osteopenia in murine Mysml deficiency

et al. 2018

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Histone modifications critically contribute to the epigenetic orchestration of bone homeostasis-in part, by modifying the access of transcription factors to specific genes involved in the osteogenic differentiation process of bone marrow mesenchymal stem cells (MSCs) and osteoblasts. Based on our previous finding that histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53 axis in hematopoiesis and tissue development, we analyzed the molecular basis of the skeletal phenotype of Mysm1-deficient mice and dissected the underlying p53-dependent and -independent mechanisms. Visible morphologic, skeletal deformations of young Mysm1-deficient mice-including a kinked and truncated tail and shortened long bones-were associated with osteopenia of long bones. On the cellular level, Mysm1-deficient primary osteoblasts displayed reduced potential to differentiate into mature osteoblasts, as indicated by decreased expression of osteogenic markers. Reduced osteogenic differentiation capacity of Mysm1-deficient osteoblasts was accompanied by an impaired induction of osteogenic transcription factor Runx2. Osteogenic differentiation of Mysm1 MSCs, however, was not compromised in vitro. In line with defective hematopoietic development of Mysm1-deficient mice, Mysm1 osteoclasts had reduced resorption activity and were more prone to apoptosis in TUNEL assays. Skeletal alterations and osteopenia of Mysm1-deficient mice were phenotypically completely rescued by simultaneous ablation of p53 in p53Mysm1 double-deficient mice-although p53 deficiency did not restore Runx2 expression in Mysm1 osteoblasts on the molecular level but, instead, enhanced proliferation and osteogenic differentiation of MSCs. In summary, our results demonstrate novel roles for Mysm1 in osteoblast differentiation and osteoclast formation, resulting in osteopenia in Mysm1-deficient mice that could be abrogated by the loss of p53 from increased osteogenic differentiation of Mysm1p53 MSCs.-Haffner-Luntzer, M., Kovtun, A., Fischer, V., Prystaz, K., Hainzl, A., Kroeger, C. M., Krikki, I., Brinker, T. J., Ignatius, A., Gatzka, M. Loss of p53 compensates osteopenia in murine Mysm1 deficiency.

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Section: Discussionmentioning

confidence: 98%

Loss of p53 compensates osteopenia in murine Mysml deficiency

et al. 2018

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“…Studies of PIDs in the region had contributed into the discovery and the understanding of large numbers of these disorders. For example, more than 12 novel PID genes were discovered through studying patients from the MENA region in the last 2 years, which include DOCK2 (35), HOIP (36), IL-17RC (37), RORC (38), RLTPR (39), POLE2 (40), NEIL3 (41), TFRC (42), INO80 (43), LAT (44), MYSM1 (45), and CD70 (46). …”

Section: Novel Pid Discoverymentioning

confidence: 99%

Primary Immunodeficiency Diseases in Highly Consanguineous Populations from Middle East and North Africa: Epidemiology, Diagnosis, and Care

Al‐Mousa

Al‐Saud

2017

Front. Immunol.

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Middle East and North Africa region (MENA)1 populations are of different ethnic origins. Consanguineous marriages are common practice with an overall incidence ranging between 20 and 50%. Primary immunodeficiency diseases (PIDs) are a group of heterogeneous genetic disorders caused by defects in the immune system that predisposes patients to recurrent infections, autoimmune diseases, and malignancies. PIDs are more common in areas with high rates of consanguineous marriage since most have an autosomal recessive mode of inheritance. Studies of PIDs in the region had contributed into the discovery and the understanding of several novel immunodeficiency disorders. Few MENA countries have established national registries that helped in estimating the prevalence and defining common PID phenotypes. Available reports from those registries suggest a predominance of combined immunodeficiency disorders in comparison to antibody deficiencies seen in other populations. Access to a comprehensive clinical immunology management services is limited in most MENA countries. Few countries had established advanced clinical immunology service, capable to provide extensive genetic testing and stem cell transplantation for various immunodeficiency disorders. Newborn screening for PIDs is an essential need in this population considering the high incidence of illness and can be implemented and incorporated into existing newborn screening programs in some MENA countries. Increased awareness, subspecialty training in clinical immunology, and establishing collaborating research centers are necessary to improve patient care. In this review, we highlight some of the available epidemiological data, challenges in establishing diagnosis, and available therapy for PID patients in the region.

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“…MYSM1 deficiency is an autosomal recessive PI that is associated with congenital bone marrow failure, myelodysplasia, genotoxic stress, developmental delay, short stature, recurrent infections, immunodeficiency affecting B cells and granulocytes, skeletal anomalies, and cataracts . NP, seen in our patient, has not been reported earlier in a child with myelodysplasia, although it was reported in association with myelodysplasia in adults.…”

Section: Discussionmentioning

confidence: 50%

“…[1][2][3][4] We report a case of NP in a child with MYSM1 (Myb-like, SWIRM, and MPN domain 1) deficiency, a newly diagnosed PI associated with bone marrow failure and developmental aberrations. 5…”

Section: Introductionmentioning

confidence: 88%