Dominant nonsense mutations in efemp1 alter vertebral and craniofacial characteristics in adult zebrafish

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Heritable Disorders of Connective Tissues (HDCT) are a heterogenous, pleiotropic group of conditions that broadly affect connective tissues. EFEMP1 is a member of the fibulin family of extracellular matrix (ECM) glycoproteins which is expressed in various human tissues. Individuals with EFEMP1 variants have recently been identified and appear to have Marfan-like characteristics. Clinical phenotypes of these individuals include hernias, advanced bone age, tall stature, myopia, joint laxity, and thin skin. EFEMP1 -associated HDCTs have been identified in individuals with biallelic and monoallelic variants. There is an urgent need to better understand the role of EFEMP1 in regulating connective tissues including bone, and the pathophysiological mechanisms underlying the spectrum of genotype-phenotype relationships seen in EFEMP1-associated HDCTs. To investigate the role of EFEMP1 in developing and adult bone, we used CRISPR-based editing to generate two efemp1 zebrafish alleles encoding for premature termination codons (PTCs) predicted to delete or severely alter the fibulin-type domain. Both alleles exhibited similar phenotypes in juvenile and adult fish. In juvenile fish, we did not identify changes in body size or vertebral development. In adults, we found significant changes in body length, bone microarchitecture, and craniofacial measurements in both heterozygous and homozygous mutant fish. These results expand our understanding of the role of efemp1 in the skeleton and highlight the potential for dominant nonsense variants to play a role in manifestation of clinical phenotypes in EFEMP1 -associated HDCTs.

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