Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome

Abstract

Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS.

Nonsense mutation in theWDR73gene is associated with Galloway-Mowat syndrome

“…The above constellation of features is consistent with Galloway-Mowat syndrome 26. While the present manuscript was under review, a study by Colin et al 27 demonstrated that loss of function mutations in WDR73 are associated with Galloway-Mowat syndrome. Colin et al 27 and the present findings demonstrate that the predicted C-terminal truncations of WDR73 protein are likely to be loss of function mutations leading to neurodevelopment defects, including CH, dysmorphic facial features, developmental delay, seizures, ocular movement defects and intellectual disability.…”

“…Colin et al 27 and the present findings demonstrate that the predicted C-terminal truncations of WDR73 protein are likely to be loss of function mutations leading to neurodevelopment defects, including CH, dysmorphic facial features, developmental delay, seizures, ocular movement defects and intellectual disability. Interestingly, unlike these clinical features, nephrotic syndrome was not present in one of the three affected children reported,27 indicating that nephrosis might be variable in patients with WDR73 mutations, and might also support the view that there are distinct forms of Galloway-Mowat syndrome 26. In general, our data support the findings of Colin et al demonstrating that WDR73 loss of function mutations may be causative for Galloway-Mowat syndrome.…”

“…We also demonstrated that the mutated human WDR73 gene was ineffective in the same in vivo rescue experiment, suggesting that the mutated WDR73 gene in the patients was likely to be a loss of function mutation. The study by Colin et al demonstrated that loss of WDR73 affected proliferation and survival of cultured fibroblasts, whereas in cultured podocytes the absence of functional WDR73 appeared to affect microtubule stability and/or dynamics,27 which could influence proliferative cell behaviour in vivo as our findings suggest.…”

“…While the present manuscript was under review, a study by Colin et al 27 demonstrated that loss of function mutations in WDR73 are associated with Galloway-Mowat syndrome. Colin et al 27 and the present findings demonstrate that the predicted C-terminal truncations of WDR73 protein are likely to be loss of function mutations leading to neurodevelopment defects, including CH, dysmorphic facial features, developmental delay, seizures, ocular movement defects and intellectual disability. Interestingly, unlike these clinical features, nephrotic syndrome was not present in one of the three affected children reported,27 indicating that nephrosis might be variable in patients with WDR73 mutations, and might also support the view that there are distinct forms of Galloway-Mowat syndrome 26.…”

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

“…Mutations in WDR62 cause autosomal recessive primary microcephaly and hypoplasia of the corpus callosum (8), and WDR73 is implicated in Galloway-Mowat syndrome characterized by microcephaly and thin corpus callosum (9). Understanding the underlying pathophysiological mechanisms of callosal disorders is critical for patient stratification and therapy development.…”