Novel TMEM53 missense variant generated a new ubiquitination site and cause Craniotubular dysplasia, Ikegawa type.

Genetic mutations in the TMEM53 gene have been linked to Craniotubular Dysplasia, Ikegawa Type (CTDI). To elucidate the etiology in a consanguineous family exhibiting the typical clinical phenotype of CTDI, trio whole exome sequencing (Trio-WES) was conducted, and a homozygous missense variant in the TMEM53 gene (NM_024587.4: c.634G > A: p.E212K) was identified. Both cellular experiments and patient blood sample analyses demonstrated that the p.E212K variant leads to the complete absence of TMEM53 protein. Further studies on ubiquitination confirmed that this variant introduced a novel ubiquitination site, causing protein degradation through the ubiquitin-proteasome system (UPS), resulting in TMEM53 protein deficiency. To our knowledge, this is the inaugural report of a missense variant creating a novel post-translational ubiquitination site that causes a Mendelian disease. This finding underscores the critical role of examining changes in post-translational modifications (PTMs) in determining the pathogenicity of gene variants.