Novel Mutations in NPHP4 in a Consanguineous Family With Histological Findings of Focal Segmental Glomerulosclerosis

Mistry, Kirtida; Ireland, James; Ng, Roland C.K.; Henderson, Joel M.; Pollak, Martin R.

doi:10.1053/j.ajkd.2007.08.009

Cited by 18 publications

(21 citation statements)

References 33 publications

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“…In this setting WER offers a powerful, non-invasive, cost-efficient diagnostic tool for arriving at a correct, unequivocal, etiology-based diagnosis. 31 Fifth, rare, genetically heterogeneous chronic kidney diseases comprise the majority of cases of CKD in children but are notoriously difficult to diagnose. The use of WER will be beneficial for these individuals, because it will be possible to accurately assign them to therapeutic studies in larger cohorts.…”

Section: Discussionmentioning

confidence: 99%

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Gee

Otto

Hurd

et al. 2014

Kidney International

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Rare single-gene disorders cause chronic disease. However, half of the 6,000 recessive single gene causes of disease are still unknown. Because recessive disease genes can illuminate, at least in part, disease pathomechanism, their identification offers direct opportunities for improved clinical management and potentially treatment. Rare diseases comprise the majority of chronic kidney disease (CKD) in children but are notoriously difficult to diagnose. Whole exome resequencing facilitates identification of recessive disease genes. However, its utility is impeded by the large number of genetic variants detected. We here overcome this limitation by combining homozygosity mapping with whole exome resequencing in 10 sib pairs with a nephronophthisisrelated ciliopathy, which represents the most frequent genetic cause of CKD in the first three decades of life. In 7 of 10 sib-ships with a histologic or ultrasonographic diagnosis of nephronophthisis-related ciliopathy we detect the causative gene. In six sib-ships we identify mutations of known nephronophthisis-related ciliopathy genes, while in two additional sib-ships we found mutations in the known CKD-causing genes SLC4A1 and AGXT as phenocopies of nephronophthisis-related ciliopathy. Thus whole exome resequencing establishes an efficient, noninvasive approach towards early detection and causation-based diagnosis of rare kidney diseases. This approach can be extended to other rare recessive disorders, thereby providing accurate diagnosis and facilitating the study of disease mechanisms.

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Section: Discussionmentioning

confidence: 99%

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Gee

Otto

Hurd

et al. 2014

Kidney International

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“…Similarly, olfactory defects have been reported in both human and mouse carriers of hypomorphic NPHP6 mutations (McEwen et al , 2007). Finally, genetic lesions in NPHP4 are in some cases associated with hearing loss (Hoefele et al , 2005; Mistry et al , 2007). The molecular basis of these abnormalities has not been clear so far.…”

Section: Discussionmentioning

confidence: 99%

Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos

Zhao

Malicki

2011

The EMBO Journal

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Cilia are required for the development and function of many organs. Efficient transport of protein cargo along ciliary axoneme is necessary to sustain these processes. Despite its importance, the mode of interaction between the intraflagellar ciliary transport (IFT) mechanism and its cargo proteins remains poorly understood. Our studies demonstrate that IFT particle components, and a Meckel-Gruber syndrome 1 (MKS1)-related, B9 domain protein, B9d2, bind each other and contribute to the ciliary localization of Inversin (Nephrocystin 2). B9d2, Inversin, and Nephrocystin 5 support, in turn, the transport of a cargo protein, Opsin, but not another photoreceptor ciliary transmembrane protein, Peripherin. Interestingly, the components of this mechanism also contribute to the formation of planar cell polarity in mechanosensory epithelia. These studies reveal a molecular mechanism that mediates the transport of selected ciliary cargos and is of fundamental importance for the differentiation and survival of sensory cells.

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“…However, the degree of foot-process effacement can be variable and thus cannot be used reliably to distinguish primary from secondary FSGS 14,15 . Moreover, In some hereditary glomerular diseases, particularly the autosomal dominant and later-onset forms of familial FSGS, such as that caused by ACTN4, TRPC6 , and INF2 mutations, the podocyte injury may be less severe and often shows a focal and segmental distribution, thus making the distinction from secondary FSGS difficult 6, 16, 9 .…”

Section: Discussionmentioning

confidence: 99%

Genetic Diagnosis in Consanguineous Families With Kidney Disease by Homozygosity Mapping Coupled With Whole-Exome Sequencing

Al-Romaih

Al-Mojalli

Al-Othman

et al. 2011

American Journal of Kidney Diseases

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Background Accurate diagnosis of the primary cause of an individual’s kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathological features despite being caused by defects in different genes. In this report we describe two consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histological features initially thought consistent with focal segmental glomerulosclerosis. Study Design Case series. Setting and participants We studied members of two apparently unrelated families from Saudi Arabia with kidney disease. Measurements Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis. Results The two apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from the affected individuals lacked any sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional PCR based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known FSGS-associated gene. Limitations The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease. Conclusions This analysis demonstrates the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology.

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Novel Mutations in NPHP4 in a Consanguineous Family With Histological Findings of Focal Segmental Glomerulosclerosis

Cited by 18 publications

References 33 publications

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies

Nephrocystins and MKS proteins interact with IFT particle and facilitate transport of selected ciliary cargos

Genetic Diagnosis in Consanguineous Families With Kidney Disease by Homozygosity Mapping Coupled With Whole-Exome Sequencing

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