A Novel PKD1 Mutation Associated With Autosomal Dominant Kidney Disease and Cerebral Cavernous Malformation

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the presence of renal cysts and specific extrarenal abnormalities. ADPKD is caused by mutations in either PKD1 or PKD2 genes that encode for integral membrane proteins Polycystin-1 (PC1) and Polycystin-2 (PC2), respectively. Extrarenal involvement includes noncystic manifestations such as dilatation of the aortic root, artery dissection and intracranial aneurysms. Cerebral cavernous malformation (CCM) is a rare vascular malformation disorder characterized by closely clustered and irregularly dilated capillaries that can be asymptomatic or cause variable neurological manifestations, such as seizures, non-specific headaches, progressive or transient focal neurologic deficits, and cerebral hemorrhages. Familial CCM is typically associated with mutations in KRIT1 (CCM1), CCM2, and PDCD10 (CCM3). The co-occurrence of ADPKD and CCM has been previously described in a single patient, although genetic analysis was not performed in this study. We report here a family with ADPKD associated with CCM in two sisters. Direct sequencing of the index patient revealed a single novel heterozygous frameshift mutation in PKD1, and lack of mutations in genes usually related to CCM. This suggests that CCM represents an additional phenotype of ADPKD.

MiR-4787-5p Regulates Vascular Smooth Muscle Cell Apoptosis by Targeting PKD1 and Inhibiting the PI3K/Akt/FKHR Pathway

“…ADPKD has been associated with cardiovascular abnormalities such as intracranial and aortic aneurysms. 19 At present, most of the literature of PC1 focuses on the pathogenesis of ADPKD, 20,21 but there are still a few studies on AD. 22 In PKD1 knockout mice, PKD1 downregulation resulted in a series of pathologic alterations in aortic walls of those mice such as latent laeouna and intramural hematoma, which are similar to human AD.…”

Familial cerebral cavernous malformation presenting with cerebellopontine angle syndrome in a patient with autosomal dominant polycystic kidney disease

“…Only 2 cases with autosomal dominant polycystic kidney disease and cavernous cerebral malformations have been reported. 4 , 5 Herein, we report the third case of cavernous cerebral malformation associated with autosomal dominant polycystic kidney disease and cerebellopontine angle syndrome.…”

Crosstalk between basal extracellular matrix adhesion and building of apical architecture during morphogenesis

“…Important effectors of integrins are Talin, which interacts with the actin cytoskeleton, and the pseudokinase integrin-linked kinase (ILK) which interacts with microtubules [MTs, ( Akhtar and Streuli, 2013 ; Klapholz et al, 2015 ; Levi et al, 2006 ; Zervas et al, 2001 )]. Interfering with integrin-mediated cell adhesion leads to morphological defects in many epithelia ( Ambrosini et al, 2019 ; Fernandes et al, 2014 ; Goodwin et al, 2016 ; Ismat et al, 2013 ; Levi et al, 2006 ; Pastor-Pareja and Xu, 2011 ; Schöck and Perrimon, 2003 ) and conditions that affect bECM composition result in severe morphogenetic defects ( Barqué et al, 2020 ; Dor-On et al, 2017 ; Jones et al, 2020 ; Messal et al, 2019 ; Thomas et al, 2018 ).…”