Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model

Takemon, Yuka; Wright, Valerie; Davenport, J Bernard; Gatti, Daniel M.; Sheehan, Susan; Letson, Kelsey; Savage, Holly; Lennon, Rachel; Korstanje, Ron

doi:10.1681/asn.2020060777

Cited by 17 publications

(18 citation statements)

References 27 publications

(56 reference statements)

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“…Other formins might be involved in other kidney disorders. For instance, Fmn1 has recently been identified as a candidate modifier gene in X-linked Alport syndrome in mice, which is a genetic disease characterized by hearing loss, hematuria and, eventually, renal failure [115].…”

Section: Monogenic Disorders Caused By Formin Mutation 21 Nephrotic Syndrome and Charcot-marie-tooth Diseasementioning

confidence: 99%

Formins in Human Disease

Labat-de-Hoz

Alonso

2021

Cells

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Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.

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Section: Monogenic Disorders Caused By Formin Mutation 21 Nephrotic Syndrome and Charcot-marie-tooth Diseasementioning

confidence: 99%

Formins in Human Disease

Labat-de-Hoz

Alonso

2021

Cells

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“…Notwithstanding the role of allelic heterogeneity in interpreting the clinical phenotype, the likely role of genetic modifiers has also been implicated [ 13 , 14 ]. AS mouse models are a useful tool for eliminating this genetic heterogeneity bias, helping in the study of the syndrome in a more restricted and relatively more homogeneous genomic background while, at the same time, allowing us to design experiments involving higher and controlled genetic heterogeneity [ 15 ]. It does not escape our attention that other parameters, including environmental factors (i.e., temperature, light-dark cycle, food, water, and other mouse room conditions), might contribute to the clinical heterogeneity observed between the mice.…”

Section: Alport Syndromementioning

confidence: 99%

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Nikolaou

Deltas

2022

Genes

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Alport syndrome is a hereditary kidney disease caused by mutations in the three genes encoding for collagen IV: COL4A3, COL4A4, and COL4A5. Several mouse models have been created for the study of this disease with variable phenotypic outcomes. This review is an up-to-date presentation of the current mouse models existing in the literature with a detailed comparison of the phenotypic features characterizing each model. Although in humans it is primarily a glomerulopathy, data suggest that in some mouse models, the initial symptoms appear in the tubule-interstitial region rather than the glomerulus. Additionally, in some other models, the severity of disease in the tubule-interstitial region is affected by the genetic background. In conclusion, the phenotypic spectrum of each model appears to be affected by the model’s genetic background, the position of the genetic alteration within the gene, and the type of the genetic alteration. Despite these disparities, mouse models recapitulate with relatively high fidelity several features of the human disease, which makes them useful for studies aimed at better understanding cellular pathomechanisms and for finding new treatments.

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“…In Alport syndrome, the rates of progression vary depending on the murine strains. Although Alport mice with a B6 genetic background develop progressive glomerular disease, the progression is slower than that in other strains [ 112 , 113 , 114 , 115 ]. These strain-dependent disparities strongly indicate the presence of modifier genes.…”

Section: Genetic Susceptibility To Tns2-deficient Nephropathymentioning

confidence: 99%

Tensin 2-deficient nephropathy: mechanosensitive nephropathy, genetic susceptibility

Sasaki

2022

Exp. Anim.

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Tensin 2 (TNS2), a focal adhesion protein, is considered to anchor focal adhesion proteins to β integrin as an integrin adaptor protein and/or serve as a scaffold to facilitate the interactions of these proteins. In the kidney, TNS2 localizes to the basolateral surface of glomerular epithelial cells, i.e., podocytes. Loss of TNS2 leads to the development of glomerular basement membrane lesions and abnormal accumulation of extracellular matrix in maturing glomeruli during the early postnatal stages. It subsequently results in podocyte foot process effacement, eventually leading to glomerulosclerosis. Histopathological features of the affected glomeruli in the middle stage of the disease include expansion of the mesangial matrix without mesangial cell proliferation. In this review, we provide an overview of TNS2-deficient nephropathy and discuss the potential mechanism underlying this mechanosensitive nephropathy, which may be applicable to other glomerulonephropathies, such as CD151-deficient nephropathy and Alport syndrome. The onset of TNS2-deficient nephropathy strictly depends on the genetic background, indicating the presence of critical modifier genes. A better understanding of molecular mechanisms of mechanosensitive nephropathy may open new avenues for the management of patients with glomerulonephropathies.

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Uncovering Modifier Genes of X-Linked Alport Syndrome Using a Novel Multiparent Mouse Model

Cited by 17 publications

References 27 publications

Formins in Human Disease

Formins in Human Disease

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

Tensin 2-deficient nephropathy: mechanosensitive nephropathy, genetic susceptibility

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