Mouse Model of X-Linked Alport Syndrome

Rheault, Michelle N.; Kren, Stefan M.; Thielen, Beth K; Mesa, Hector; Crosson, John T.; Thomas, William; Sado, Yoshikazu; Kashtan, Clifford E.; Segal, Yoav

doi:10.1097/01.asn.0000130562.90255.8f

Cited by 124 publications

(100 citation statements)

References 36 publications

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“…16 Glomeruli of Myo1e-KO mice also exhibit GBM thickening and disorganization, which is reminiscent of structural changes observed in some of the inherited renal diseases, such as Alport syndrome. 17,18 Analysis of renal function in Myo1e-KO mice revealed severe proteinuria as well as elevated BUN levels, both of which indicate impaired renal filtration. Although impaired glomerular filtration may also be caused by the deposition of antibodies or antibody-antigen complexes in the glomerulus, we did not observe immune complex deposits by EM.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Myosin 1e Promotes Podocyte Injury

Krendel¹,

Kim²,

Willinger³

et al. 2009

Journal of the American Society of Nephrology

106

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Myosin 1e (Myo1e) is one of two Src homology 3 domain-containing "long-tailed" type I myosins in vertebrates, whose functions in health and disease are incompletely understood. Here, we demonstrate that Myo1e localizes to podocytes in the kidney. We generated Myo1e-knockout mice and found that they exhibit proteinuria, signs of chronic renal injury, and kidney inflammation. At the ultrastructural level, renal tissue from Myo1e-null mice demonstrates changes characteristic of glomerular disease, including a thickened and disorganized glomerular basement membrane and flattened podocyte foot processes. These observations suggest that Myo1e plays an important role in podocyte function and normal glomerular filtration.

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Section: Discussionmentioning

confidence: 99%

Disruption of Myosin 1e Promotes Podocyte Injury

Krendel¹,

Kim²,

Willinger³

et al. 2009

Journal of the American Society of Nephrology

106

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“…Involvement of COL4A6 in hereditary disease has been shown only in intergenic rearrangements simultaneously affecting the closely linked COL4A5 and COL4A6 genes in patients expressing Alport syndrome with leiomyomatosis (Zhou et al 1993;Renieri et al 1994;Garcia-Torres et al 2000;Mothes et al 2002;Anker et al 2003). In the mouse, mutations of Col4a1 (Gould et al 2005;Van Agtmael et al 2005), Col4a3 (Cosgrove et al 1996;Miner and Sanes 1996), and Col4a5 (Rheault et al 2004) have been recovered or constructed. In addition, a targeted mutation that ablates the closely linked Col4a1 and Col4a2 genes (Pö schl et al ) and an insertional mutation that simultaneously disrupts the closely linked Col4a3 and Col4a4 genes (Lu et al 1999) have been generated.…”

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confidence: 99%

Type IV Procollagen Missense Mutations Associated With Defects of the Eye, Vascular Stability, the Brain, Kidney Function and Embryonic or Postnatal Viability in the Mouse, Mus musculus: An Extension of the Col4a1 Allelic Series and the Identification of the First Two Col4a2 Mutant Alleles

Favor¹,

Gloeckner

Janik³

et al. 2007

Genetics

121

123

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The basement membrane is important for proper tissue development, stability, and physiology. Major components of the basement membrane include laminins and type IV collagens. The type IV procollagens Col4a1 and Col4a2 form the heterotrimer [a1(IV)] 2 [a2(IV)], which is ubiquitously expressed in basement membranes during early developmental stages. We present the genetic, molecular, and phenotypic characterization of nine Col4a1 and three Col4a2 missense mutations recovered in random mutagenesis experiments in the mouse. Heterozygous carriers express defects in the eye, the brain, kidney function, vascular stability, and viability. Homozygotes do not survive beyond the second trimester. Ten mutations result in amino acid substitutions at nine conserved Gly sites within the collagenous domain, one mutation is in the carboxy-terminal noncollagenous domain, and one mutation is in the signal peptide sequence and is predicted to disrupt the signal peptide cleavage site. Patients with COL4A2 mutations have still not been identified. We suggest that the spontaneous intraorbital hemorrhages observed in the mouse are a clinically relevant phenotype with a relatively high predictive value to identify carriers of COL4A1 or COL4A2 mutations.

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“…Mutations that prevent the expression of any one of these three type IV collagen chains in humans cause Alport syndrome, characterized by proteinuria, focal segmental glomerulosclerosis, and end-stage renal failure (Barker et al 1990;Lemmink et al 1994;Mochizuki et al 1994). Mutations in type IV collagen a5 in dogs (Zheng et al 1994) and mutations of a3 (Cosgrove et al 1996), a3 and a4 (Lu et al 1999), or a5 (Rheault et al 2004) in mice also result in glomerular basement membrane abnormalities that culminate in end-stage renal disease.…”

Section: Resultsmentioning

confidence: 99%

Rapid Identification of a Disease Allele in Mouse Through Whole Genome Sequencing and Bulk Segregation Analysis

Arnold¹,

Xia²,

Lin³

et al. 2011

Genetics

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In a pedigree of C57BL/6J mice homozygous for germline mutations induced by the mutagen N-ethyl-N-nitrosourea (ENU), numerous animals died under specific pathogen-free (SPF) conditions between 6 and 7 months of age. Death was caused by nephritic syndrome, which progressed to renal failure associated with focal segmental glomerulosclerosis. To identify the mutation responsible for renal disease, we sequenced genomic DNA from an affected animal using the Applied Biosystems SOLiD sequencing platform. Approximately 74% of the nucleotides comprising coding sequences and splice junctions in the mouse genome were covered at least three times. Within this portion of the genome, 64 discrepancies were flagged as potential homozygous mutations and 82 were flagged as potential heterozygous mutations. A total of 10 of these calls, all homozygous, were validated by capillary sequencing. One of the validated mutations disrupted splicing of the Col4a4 transcript. Genetic mapping by bulk segregation analysis excluded all mutations but this one as the cause of renal disease in Aoba mice. Col4a4 has not been targeted in the mouse, and this strain, named Aoba, represents the first functionally null allele in this species. Our study demonstrates the speed and utility of whole genome sequencing coupled with low resolution meiotic mapping as a means of identifying causative mutations induced by ENU.T HE laboratory mouse has been used as a model organism in forward genetic studies in which the point mutagen, N-ethyl-N-nitrosourea (ENU), is applied to generate phenotype, and positional cloning is used to find causative mutations. The availability of an annotated reference genome sequence for the C57BL/6J strain has greatly accelerated the identification of point mutations. However, it remains necessary to outcross mutations and formally map them. In the past, ''fine mapping'' was often needed to define a critical region that could be directly sequenced at the genomic level to identify causative mutations.Coarse mapping to a large chromosomal region coupled with whole genome sequencing using massively parallel short-read sequencing platforms may be sufficient to exclude all but a single ENU-induced mutation in a defined genetic background. Whole genome sequencing may thereby eliminate the need for fine mapping of mutations and exploration of large critical regions, both expensive and time-consuming steps in positional cloning. Whereas a year or more was formerly required to identify causative mutations, a month or less may now be needed.Over the past 4 years, such sequencing platforms, including the Roche (454) GS FLX sequencer, Illumina genome analyzer, and Applied Biosystems SOLiD sequencer, have become available. They all have in common the capability to process millions of sequence reads in parallel at relatively low cost and are being applied in a number of ways, from resequencing whole genomes, as in The 1000 Genomes Project and The Exome Project Here we have applied whole genome sequencing using the Applied Biosystems SOLi...

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Mouse Model of X-Linked Alport Syndrome

Cited by 124 publications

References 36 publications

Disruption of Myosin 1e Promotes Podocyte Injury

Disruption of Myosin 1e Promotes Podocyte Injury

Type IV Procollagen Missense Mutations Associated With Defects of the Eye, Vascular Stability, the Brain, Kidney Function and Embryonic or Postnatal Viability in the Mouse, Mus musculus: An Extension of the Col4a1 Allelic Series and the Identification of the First Two Col4a2 Mutant Alleles

Rapid Identification of a Disease Allele in Mouse Through Whole Genome Sequencing and Bulk Segregation Analysis

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