A zebrafish model of growth hormone insensitivity syndrome with immune dysregulation 1 (GHISID1)

Abstract

Signal transducer and activator of transcription (STAT) proteins act downstream of cytokine receptors to facilitate changes in gene expression that impact a range of developmental and homeostatic processes. Patients harbouring loss-of-function (LOF) STAT5B mutations exhibit postnatal growth failure due to lack of responsiveness to growth hormone as well as immune perturbation, a disorder called growth hormone insensitivity syndrome with immune dysregulation 1 (GHISID1). This study aimed to generate a zebrafish model of this disease by targeting the stat5.1 gene using CRISPR/Cas9 and characterising the effects on growth and immunity. The zebrafish Stat5.1 mutants were smaller, but exhibited increased adiposity, with concomitant dysregulation of growth and lipid metabolism genes. The mutants also displayed impaired lymphopoiesis with reduced T cells throughout the lifespan, along with broader disruption of the lymphoid compartment in adulthood, including evidence of T cell activation. Collectively, these findings confirm that zebrafish Stat5.1 mutants mimic the clinical impacts of human STAT5B LOF mutations, establishing them as a model of GHISID1.

Janus Kinase 3 (JAK3): A Critical Conserved Node in Immunity Disrupted in Immune Cell Cancer and Immunodeficiency

“…Zebrafish carrying an inactivating mutation of Il-7rα exhibited reduced T cells, but unaffected B cells, again similar to humans, with NK cells not characterized in this study [ 89 ]. STAT5B-deficient humans also displayed immunodeficiency and growth defects [ 102 ], which closely resembled those observed in Zebrafish Stat5.1 LOF mutants [ 103 ]. In contrast, an activating zebrafish Stat5.1 N649H mutant impacted both lymphoid and myeloid lineages [ 104 ], replicating features of the STAT5B N649H-mediated disease observed in mice [ 105 ].…”

In Search of a Target Gene for a Desirable Phenotype in Aquaculture: Genome Editing of Cyprinidae and Salmonidae Species

“…Bernard-Soulier syndrome [36], Xia-Gibbs syndrome [37], Lee syndrome [38], Laron syndrome [39], Aicardi-Gutierrez syndrome [40], Finnish-type nephrotic syndrome [41], fragile cornea syndrome [42], multicentric carpotarsal osteolysis syndrome [43], Bietti crystalline dystrophy [44], sarcoglycanopathy [45], autosomal recessive microcephaly [46], sphingolipidosess [47], and mitochondrial diseases caused by polg gene mutations [48].…”

“…In creating disease models, known mutations in genes that cause particular genetic syndromes in humans are obtained, such as muscle laminopathy [ 31 ], Charlevoix-Saguenay spastic ataxia [ 32 ], Marfan syndrome [ 33 ], Sanfilippo syndrome [ 34 ], Joubert syndrome [ 35 ], Bernard-Soulier syndrome [ 36 ], Xia-Gibbs syndrome [ 37 ], Lee syndrome [ 38 ], Laron syndrome [ 39 ], Aicardi-Gutierrez syndrome [ 40 ], Finnish-type nephrotic syndrome [ 41 ], fragile cornea syndrome [ 42 ], multicentric carpotarsal osteolysis syndrome [ 43 ], Bietti crystalline dystrophy [ 44 ], sarcoglycanopathy [ 45 ], autosomal recessive microcephaly [ 46 ], sphingolipidosess [ 47 ], and mitochondrial diseases caused by polg gene mutations [ 48 ].…”