Phenotypic variability in distal acidification defects associated with WDR72 mutations

Khandelwal, Priyanka; Mahesh,; Mathur, Vijay Prakash; Raut, Sumantra; Geetha, Thenral S; Nair, Sandhya; Hari, Pankaj; Sinha, Aditi; Bagga, Arvind

doi:10.1007/s00467-020-04747-5

Cited by 18 publications

(20 citation statements)

References 29 publications

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“…NP1 cells were generated from freshly isolated tubuli from a C57BL/6J mouse, representing a cell type of the distal tubular kidney epithelial cells 24 . Our findings in WDR72 expression suggest a molecular connection between ectoderm-derived ameloblasts and kidney epithelial cells, supporting the recent reports that WDR72 mutations are associated with distal renal tubular acidosis and Amelogenesis Imperfecta 25 – 28 .…”

Section: Discussionsupporting

confidence: 91%

Identification of the C-terminal region in Amelogenesis Imperfecta causative protein WDR72 required for Golgi localization

Husein

Alamoudi

Ohyama

et al. 2022

Sci Rep

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Amelogenesis Imperfecta (AI) represents a group of hereditary conditions that manifest tooth enamel defects. Several causative mutations in the WDR72 gene have been identified and patients with WDR72 mutations have brown (or orange-brown) discolored enamel, rough enamel surface, early loss of enamel after tooth eruption, and severe attrition. Although the molecular function of WDR72 is not yet fully understood, a recent study suggested that WDR72 could be a facilitator of endocytic vesicle trafficking, which appears inconsistent with the previously reported cytoplasmic localization of WDR72. Therefore, the aims of our study were to investigate the tissues and cell lines in which WDR72 was expressed and to further determine the sub-cellular localization of WDR72. The expression of Wdr72 gene was investigated in mouse tissues and cell lines. Endogenous WDR72 protein was detected in the membranous fraction of ameloblast cell lines in addition to the cytosolic fraction. Sub-cellular localization studies supported our fractionation data, showing WDR72 at the Golgi apparatus, and to a lesser extent, in the cytoplasmic area. In contrast, a WDR72 AI mutant form that lacks its C-terminal region was exclusively detected in the cytoplasm. In addition, our studies identified a putative prenylation/CAAX motif within the last four amino acids of human WDR72 and generated a WDR72 variant, called CS mutant, in which the putative motif was ablated by a point mutation. Interestingly, mutation of the putative CAAX motif impaired WDR72 recruitment to the Golgi. Cell fractionation assays confirmed subcellular distribution of wild-type WDR72 in both cytosolic and membranous fractions, while the WDR72 AI mutant and CS mutant forms were predominantly detected in the cytosolic fraction. Our studies provide new insights into the subcellular localization of WDR72 and demonstrate a critical role for the C-terminal CAAX motif in regulating WDR72 recruitment to the Golgi. In accordance with structural modelling studies that classified WDR72 as a potential vesicle transport protein, our findings suggest a role for WDR72 in vesicular Golgi transport that may be key to understanding the underlying cause of AI.

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Section: Discussionsupporting

confidence: 91%

Identification of the C-terminal region in Amelogenesis Imperfecta causative protein WDR72 required for Golgi localization

Husein

Alamoudi

Ohyama

et al. 2022

Sci Rep

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“…Recessive mutations in WDR72 have been associated with amelogenesis imperfecta, 50 and distal renal tubular acidosis. 51,52 By GWAS, variants in WDR72 have been associated with kidney function and CKD, 14,41,53 urine pH, 42 and risk of kidney stones. 42,43 In CKDGen, the index SNP at WDR72 was associated with blood urea nitrogen.…”

Section: Discussionmentioning

confidence: 99%

“…WDR72 is highly expressed in the kidney, although we found it clustered in the collecting ducts. Recessive mutations in WDR72 have been associated with amelogenesis imperfecta, 50 and distal renal tubular acidosis 51 , 52 . By GWAS, variants in WDR72 have been associated with kidney function and CKD, 14 , 41 , 53 urine pH, 42 and risk of kidney stones 42 , 43 .…”

Section: Discussionmentioning

confidence: 99%

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Joseph

Mariniello

Yoshifuji

et al. 2022

JASN

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BackgroundUromodulin, the most abundant protein excreted in normal urine, plays major roles in kidney physiology and disease. The mechanisms regulating the urinary excretion of uromodulin remain essentially unknown.MethodsWe conducted a meta-analysis of genome-wide association studies for raw (uUMOD) and indexed to creatinine (uUCR) urinary levels of uromodulin in 29,315 individuals of European ancestry from 13 cohorts. We tested the distribution of candidate genes in kidney segments and investigated the effects of keratin-40 (KRT40) on uromodulin processing.ResultsTwo genome-wide significant signals were identified for uUMOD: a novel locus (P 1.24E–08) over the KRT40 gene coding for KRT40, a type 1 keratin expressed in the kidney, and the UMOD-PDILT locus (P 2.17E–88), with two independent sets of single nucleotide polymorphisms spread over UMOD and PDILT. Two genome-wide significant signals for uUCR were identified at the UMOD-PDILT locus and at the novel WDR72 locus previously associated with kidney function. The effect sizes for rs8067385, the index single nucleotide polymorphism in the KRT40 locus, were similar for both uUMOD and uUCR. KRT40 colocalized with uromodulin and modulating its expression in thick ascending limb (TAL) cells affected uromodulin processing and excretion.ConclusionsCommon variants in KRT40, WDR72, UMOD, and PDILT associate with the levels of uromodulin in urine. The expression of KRT40 affects uromodulin processing in TAL cells. These results, although limited by lack of replication, provide insights into the biology of uromodulin, the role of keratins in the kidney, and the influence of the UMOD-PDILT locus on kidney function.

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“…Low bone mineral density was probably due to hypophosphataemic osteomalacia. Recurrent bilateral nephrolithiasis prompted us to consider the possibility of dRTA, as mutation of WDR72 can be associated with both AI and nephrolithiasis/nephrocalcinosis secondary to inherited dRTA 5. Metabolic acidosis in WDR72 defect is mild and variable in intensity; hence systemic acid loading is often required to unveil defective distal H + secretion.…”

Section: Differential Diagnosismentioning

confidence: 99%

Hypoplastic amelogenesis imperfecta, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia: a triad of FAM20A-related enamel renal syndrome

et al. 2022

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Enamel renal syndrome (ERS) due to loss of function (LOF) mutation of FAM20A gene typically consists of hypoplastic amelogenesis imperfecta (AI) and bilateral nephrolithiasis/nephrocalcinosis. Recent evidence suggests that FAM20A interacts with FAM20C and increases its activity; thus LOF mutation of FAM20A leads to impaired FAM20C action. FAM20C, a golgi casein kinase, phosphorylates fibroblast growth factor (FGF)-23, prevents its glycosylation and makes it more susceptible to degradation by furine proteases. Consequently, inactivating mutations of FAM20C lead to increased concentration of bioactive and intact FGF-23 in circulation and resultant hypophosphataemia. LOF mutation of FAM20A, thus, might also be associated with FGF-23-mediated hypophosphataemia; however, such an association has never been reported in the literature. We describe, for the first time, a triad of AI, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia in LOF mutation of FAM20A. We suggest that serum phosphate should be measured in all patients with ERS to avoid metabolic and skeletal complications of undiagnosed, hence untreated hypophosphataemia.

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Phenotypic variability in distal acidification defects associated with WDR72 mutations

Cited by 18 publications

References 29 publications

Identification of the C-terminal region in Amelogenesis Imperfecta causative protein WDR72 required for Golgi localization

Identification of the C-terminal region in Amelogenesis Imperfecta causative protein WDR72 required for Golgi localization

Meta-GWAS Reveals Novel Genetic Variants Associated with Urinary Excretion of Uromodulin

Hypoplastic amelogenesis imperfecta, bilateral nephrolithiasis and FGF-23-mediated hypophosphataemia: a triad of FAM20A-related enamel renal syndrome

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