DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Abstract

Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom present with CAKUT/GD. Studies in Xenopus embryos demonstrate that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by co-injecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss of function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

“…We noted, for the first time, the importance of skin manifestations and especially atopic dermatitis. We also found some genital abnormalies, as already reported (Blackburn et al , 2019b) ( Supplementary text) . We used recurrent features to establish a “DYRK1A-clinical score” (CS DYRK1A ) on 20 points ( Figure 1A ), which aims to reflect specificity rather than severity of the phenotype.…”

“…Few years after, the first frameshift variant was described in a patient with similar features (Courcet et al , 2012). The clinical spectrum associated with DYRK1A pathogenic variants ( MRD7 for Mental Retardation 7 in OMIM ) was further refined with the publication of additional patients, presenting suggestive facial dysmorphism, severe speech impairment and feeding difficulty, while epilepsy and prenatal microcephaly were not always present (Bronicki et al , 2015; Blackburn et al , 2019a; van Bon et al , 2011, 2016; O’Roak et al , 2012; Courcet et al , 2012; Okamoto et al , 2015; Iglesias et al , 2014; Ruaud et al , 2015; Ji et al , 2015; Rump et al , 2016; Luco et al , 2016; Murray et al , 2017; Evers et al , 2017; Lee et al , 2020a; Dang et al , 2018; Qiao et al , 2019; Ernst et al , 2020; Tran et al , 2020; Møller et al , 2008; Fujita et al , 2010; Oegema et al , 2010; Yamamoto et al , 2011; Valetto et al , 2012; Kim et al , 2017; Meissner et al , 2020; Matsumoto et al , 1997). Pathogenic variants were also identified in cohorts of individuals with ASD (O’Roak et al , 2012), but all have ID (Earl et al , 2017).…”

Parallel in vivo analysis of large-effect autism genes implicates cortical neurogenesis and estrogen in risk and resilience

“…Combining all mutants, telencephalon size variance was significantly changed following ASD risk gene mutation (p < 0.0001 by a Brown-Forsythe test), whereas variance in mesencephalon, diencephalon, and rhombencephalon sizes was not ( Figures S3A and S3B). We used a well-characterized morpholino (dyrk1a MO) (Blackburn et al, 2019) and a pharmacological inhibitor (harmine) (Gö ckler et al, 2009) to validate our findings for the gene dyrk1a ( Figures S3C-S3F), and injection of human DYRK1A (hDYRK1A-GFP) rescued the Xenopus dyrk1a CRISPR phenotype (Figures 2F,2G,and 2I).…”

Aquatic models of human ciliary diseases

“…Since the cilia are thought to stall cell division, loss of cilia in DYRK1A related intellectual disability syndrome patients may lead to inappropriate cell division (Plotnikova, Pugacheva, & Golemis, 2009; Tucker, Pardee, & Fujiwara, 1979). Like many other ciliopathies loss of dyrk1a or many other cilia related genes involved in neural development are also associated with kidney abnormalities (Blackburn et al, 2019; Parisi et al, 2006).…”