A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

Kristian Assing; Sofie E. Jørgensen; Katrine S. Sandgaard; Kerstin De Keukeleere; Marie B.-Hansen; Mikkel S. Petersen; Ulla B. Hartling; Thanis M.K.de Vaal; Christian Nielsen; Marianne A. Jakobsen; Eleanor Watt; Stuart Adams; Qin Hao; Christina Fagerberg; Trine H. Mogensen

doi:10.1007/s10875-023-01561-0

A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

Kristian Assing^*, Sofie E. Jørgensen, Katrine S. Sandgaard, Kerstin De Keukeleere, Marie B.-Hansen, Mikkel S. Petersen, Ulla B. Hartling, Thanis M.K.de Vaal, Christian Nielsen, Marianne A. Jakobsen, Eleanor Watt, Stuart Adams, Qin Hao, Christina Fagerberg, Trine H. Mogensen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Abstract

Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

Originalsprog	Engelsk
Tidsskrift	Journal of Clinical Immunology
Vol/bind	43
Nummer	8
Sider (fra-til)	1927-1940
Antal sider	14
ISSN	0271-9142
DOI	https://doi.org/10.1007/s10875-023-01561-0
Status	Udgivet - nov. 2023

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Assing, K., Jørgensen, S. E., Sandgaard, K. S., De Keukeleere, K., B.-Hansen, M., Petersen, M. S., Hartling, U. B., Vaal, T. M. K. D., Nielsen, C., Jakobsen, M. A., Watt, E., Adams, S., Hao, Q., Fagerberg, C., & Mogensen, T. H. (2023). A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity. Journal of Clinical Immunology, 43(8), 1927-1940. https://doi.org/10.1007/s10875-023-01561-0

@article{01052c232afb4020822b60e6ba089294,

title = "A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity",

abstract = "Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.",

keywords = "CDC42, HPV carcinogenesis, IL7 receptor, Inborn error of immunity, Lymphopenia, Mosaic, T cell receptor diversity, Newborn screening, p21-Activated Kinases, Receptors, Antigen, T-Cell/genetics, Signal Transduction, Humans, Interleukin-7/genetics, Infant, Newborn, Apoptosis",

author = "Kristian Assing and J{\o}rgensen, {Sofie E.} and Sandgaard, {Katrine S.} and {De Keukeleere}, Kerstin and Marie B.-Hansen and Petersen, {Mikkel S.} and Hartling, {Ulla B.} and Vaal, {Thanis M.K.de} and Christian Nielsen and Jakobsen, {Marianne A.} and Eleanor Watt and Stuart Adams and Qin Hao and Christina Fagerberg and Mogensen, {Trine H.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = nov,

doi = "10.1007/s10875-023-01561-0",

language = "English",

volume = "43",

pages = "1927--1940",

journal = "Journal of Clinical Immunology",

issn = "0271-9142",

publisher = "Springer",

number = "8",

}

Assing, K, Jørgensen, SE , Sandgaard, KS , De Keukeleere, K, B.-Hansen, M, Petersen, MS, Hartling, UB, Vaal, TMKD, Nielsen, C, Jakobsen, MA, Watt, E, Adams, S, Hao, Q, Fagerberg, C & Mogensen, TH 2023, 'A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity', Journal of Clinical Immunology, bind 43, nr. 8, s. 1927-1940. https://doi.org/10.1007/s10875-023-01561-0

A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity. / Assing, Kristian; Jørgensen, Sofie E.; Sandgaard, Katrine S. et al.
I: Journal of Clinical Immunology, Bind 43, Nr. 8, 11.2023, s. 1927-1940.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

AU - Assing, Kristian

AU - Jørgensen, Sofie E.

AU - Sandgaard, Katrine S.

AU - De Keukeleere, Kerstin

AU - B.-Hansen, Marie

AU - Petersen, Mikkel S.

AU - Hartling, Ulla B.

AU - Vaal, Thanis M.K.de

AU - Nielsen, Christian

AU - Jakobsen, Marianne A.

AU - Watt, Eleanor

AU - Adams, Stuart

AU - Hao, Qin

AU - Fagerberg, Christina

AU - Mogensen, Trine H.

PY - 2023/11

Y1 - 2023/11

N2 - Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

AB - Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.

KW - CDC42

KW - HPV carcinogenesis

KW - IL7 receptor

KW - Inborn error of immunity

KW - Lymphopenia

KW - Mosaic, T cell receptor diversity

KW - Newborn screening

KW - p21-Activated Kinases

KW - Receptors, Antigen, T-Cell/genetics

KW - Signal Transduction

KW - Humans

KW - Interleukin-7/genetics

KW - Infant, Newborn

KW - Apoptosis

UR - http://www.scopus.com/inward/record.url?scp=85167828831&partnerID=8YFLogxK

U2 - 10.1007/s10875-023-01561-0

DO - 10.1007/s10875-023-01561-0

M3 - Journal article

C2 - 37581646

AN - SCOPUS:85167828831

SN - 0271-9142

VL - 43

SP - 1927

EP - 1940

JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

IS - 8

ER -

A Novel CDC42 Variant with Impaired Thymopoiesis, IL-7R Signaling, PAK1 Binding, and TCR Repertoire Diversity

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