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Abstract/Summary
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<jats:title>Abstract</jats:title><jats:sec>
<jats:title>Background/Objectives</jats:title>
<jats:p>Rare genetic disorders causing specific congenital developmental abnormalities often manifest in single families. Investigation of disease-causing molecular features are most times lacking, although these investigations may open novel therapeutic options for patients. In this study, we aimed to identify the genetic cause in an Iranian patient with severe skeletal dysplasia and to model its molecular function in zebrafish embryos.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>The proband displays short stature and multiple skeletal abnormalities, including mesomelic dysplasia of the arms with complete humero-radio-ulna synostosis, arched clavicles, pelvic dysplasia, short and thin fibulae, proportionally short vertebrae, hyperlordosis and mild kyphosis. Exome sequencing of the patient revealed a novel homozygous c.374G > T, p.(Arg125Leu) missense variant in <jats:italic>MSGN1</jats:italic> (NM_001105569). MSGN1, a basic-Helix–Loop–Helix transcription factor, plays a crucial role in formation of presomitic mesoderm progenitor cells/mesodermal stem cells during early developmental processes in vertebrates. Initial in vitro experiments show protein stability and correct intracellular localization of the novel variant in the nucleus and imply retained transcription factor function. To test the pathogenicity of the detected variant, we overexpressed wild-type and mutant <jats:italic>msgn1</jats:italic> mRNA in zebrafish embryos and analyzed <jats:italic>tbxta</jats:italic> (<jats:italic>T/brachyury/ntl</jats:italic>). Overexpression of wild-type or mutant <jats:italic>msgn1</jats:italic> mRNA significantly reduces <jats:italic>tbxta</jats:italic> expression in the tailbud compared to control embryos. Mutant <jats:italic>msgn1</jats:italic> mRNA injected embryos depict a more severe effect, implying a gain-of-function mechanism. In vivo analysis on embryonic development was performed by clonal <jats:italic>msgn1</jats:italic> overexpression in zebrafish embryos further demonstrated altered cell compartments in the presomitic mesoderm, notochord and pectoral fin buds. Detection of ectopic <jats:italic>tbx6</jats:italic> and <jats:italic>bmp2</jats:italic> expression in these embryos hint to affected downstream signals due to Msgn1 gain-of-function.</jats:p>
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<jats:title>Conclusion</jats:title>
<jats:p>In contrast to loss-of-function effects described in animal knockdown models, gain-of-function of MSGN1 explains the only mildly affected axial skeleton of the proband and rather normal vertebrae. In this context we observed notochord bending and potentially disruption of pectoral fin buds/upper extremity after overexpression of <jats:italic>msgn1</jats:italic> in zebrafish embryos. The latter might result from Msgn1 function on mesenchymal stem cells or on chondrogenesis in these regions. In addition, we detected ectopic <jats:italic>tbx6</jats:italic> and <jats:italic>bmp2a</jats:italic> expression after gain of Msgn1 function in zebrafish, which are interconnected to short stature, congenital scoliosis, limb shortening and prominent skeletal malformations in patients. Our findings highlight a rare, so far undescribed skeletal dysplasia syndrome associated with a gain-of-function mutation in <jats:italic>MSGN1</jats:italic> and hint to its molecular downstream effectors.</jats:p>
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Hinweis
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