Abstract
DBR1 encodes the only known human lariat debranching enzyme and its deficiency has been found to cause an autosomal recessive inborn error of immunity characterized by pediatric brainstem viral-induced encephalitis (MIM 619441). We describe a distinct allelic disorder caused by a founder recessive DBR1 variant in four families (DBR1(NM_016216.4):c.200A > G (p.Tyr67Cys)). Consistent features include prematurity, severe intrauterine growth deficiency, congenital ichthyosis-like presentation (collodion membrane, severe skin peeling and xerosis), and death before the first year of life. Patient-derived fibroblasts displayed the characteristic accumulation of intron lariats in their RNA as revealed by targeted and untargeted analysis, in addition to a marked reduction of DBR1 on immunoblot analysis. We propose a novel DBR1-related developmental disorder that is distinct from DBR1-related encephalitis susceptibility and highlight the apparent lack of correlation with the degree of DBR1 deficiency.
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We thank the study families for their enthusiastic participation.
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The referring physicians (ZR, FAM, FA, HAA) provided clinical information and images. Material preparation, data collection and analysis, and functional validation were performed by (MS, JM, MA, HES, RA-A, MR, SL and FA). PB, AB-A, FSA and all authors contributed to the writing of the manuscript, as well the final version was read and approved by all authors. FSA supervised the work in its entirety.
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439_2023_2597_MOESM3_ESM.pptx
Fig S1: IGV Sashimi plot view of an intronic region in the GRK5, PDCD11, DZIP1L, TEP1, LRCH1, BRWD1 genes showing a higher intronic reads accumulation in the patient compared to the control. The low coverage in the intron-exon junction regions suggests the presence of lariat RNA. Fig S2: Panel showing expression of DBR1 in different tissues. Supplementary file3 (PPTX 571 KB)
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Shamseldin, H.E., Sadagopan, M., Martini, J. et al. A founder DBR1 variant causes a lethal form of congenital ichthyosis. Hum. Genet. 142, 1491–1498 (2023). https://doi.org/10.1007/s00439-023-02597-3
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DOI: https://doi.org/10.1007/s00439-023-02597-3