Mutations in WDR19 encoding the intraflagellar transport component IFT144 cause a broad spectrum of ciliopathies

Fehrenbach, Henry; Decker, Christian; Eisenberger, Tobias; Frank, Valeska; Hampel, Tobias; Walden, Ulrike; Amann, Kerstin; Krüger-Stollfuß, Ingrid; Bolz, Hanno J.; Häffner, Karsten; Pöhl, Martin; Bergmann, Carsten

doi:10.1007/s00467-014-2762-2

Cited by 36 publications

(26 citation statements)

References 12 publications

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“…The association of NPHP with retinal degeneration (Senior - Løken syndrome) is most frequent and occurs in ~10% of all patients with NPHP (Loken et al 1961; Senior et al 1961). Furthermore, NPHP can be accompanied by oculomotor apraxia (Cogan syndrome), (Betz et al 2000) by cerebellar vermis hypoplasia and retinal coloboma (Joubert syndrome), (Saraiva and Baraitser 1992; Valente et al 2006) by liver fibrosis, (Boichis et al 1973) by ectodermal dysplasia (Sensenbrenner syndrome, oral-facial-digital syndrome type I), (Bredrup et al 2011; Fehrenbach et al 2014) and in rare cases by congenital heart defects (Otto et al 2003a; Rajagopalan et al 2016). Skeletal malformations associated with renal ciliopathies include thoracic dystrophy (Jeune syndrome), (Halbritter et al 2013a; Huber et al 2013; Schmidts et al 2013a) poly-, and brachydactyly, and cone-shaped epiphysis (Mainzer - Saldino syndrome) (Perrault et al 2012).…”

Section: Extrarenai Manifestations Of Nphp-related Ciliopathiesmentioning

confidence: 99%

Ciliopathies

Braun¹,

Hildebrandt

2016

Cold Spring Harb Perspect Biol

346

335

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NPHP-related ciliopathies (NPHP-RC) are a group of inherited diseases that affect genes encoding proteins that localize to primary cilia or centrosomes. With few exceptions, ciliopathies are inherited in an autosomal recessive manner, and affected individuals manifest early during childhood or adolescence. NPHP-RC are genetically very heterogeneous, and currently mutations in more than 90 genes have been described as single-gene causes. The phenotypes of NPHP-RC are very diverse, and include cystic-fibrotic kidney disease, brain developmental defects, retinal degeneration, skeletal deformities, facial dysmorphism, and in some cases, laterality defects, and congenital heart disease. Mutations in the same gene can give rise to diverse phenotypes depending on the mutated allele. At the same time, there is broad phenotypic overlap between different monogenic genes. The identification of monogenic causes of ciliopathies has further the understanding of molecular mechanism and cellular pathways involved in the pathogenesis.

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Section: Extrarenai Manifestations Of Nphp-related Ciliopathiesmentioning

confidence: 99%

Ciliopathies

Braun¹,

Hildebrandt

2016

Cold Spring Harb Perspect Biol

346

335

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“…In Meckel-Gruber syndrome, the complete loss of MKS1 leads to a marked defect in cilia formation and could result in severe mislocalization of ciliary proteins 55 . This example is characteristic of the phenotypic variability seen with mutations in ciliopathy-associated genes 58,59 . Nonsense-associated alternative splicing, a mechanism whereby detrimentally mutated exons are spliced out of the final gene transcript, partially explains phenotypic variability in patients with CEP290-related ciliopathies 60,61 (FIG.…”

Section: Expansions Within Disease Categoriesmentioning

confidence: 95%

The expanding phenotypic spectra of kidney diseases: insights from genetic studies

et al. 2016

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Next-generation sequencing (NGS) has led to the identification of previously unrecognized phenotypes associated with classic kidney disease genes. In addition to improving diagnostics for genetically heterogeneous diseases and enabling a faster rate of gene discovery, NGS has enabled an expansion and redefinition of nephrogenetic disease categories. Findings from these studies raise the question of whether disease diagnoses should be made on clinical grounds, on genetic evidence or a combination thereof. Here, we discuss the major kidney disease-associated genes and gene categories for which NGS has expanded the phenotypic spectrum. For example, COL4A3-5 genes, which are classically associated with Alport syndrome, are now understood to also be involved in the aetiology of focal segmental glomerulosclerosis. DGKE, which is associated with nephrotic syndrome, is also mutated in patients with atypical haemolytic uraemic syndrome. We examine how a shared genetic background between diverse clinical phenotypes can provide insight into the function of genes and novel links with essential pathophysiological mechanisms. In addition, we consider genetic and epigenetic factors that contribute to the observed phenotypic heterogeneity of kidney diseases and discuss the challenges in the interpretation of genetic data. Finally, we discuss the implications of the expanding phenotypic spectra associated with kidney disease genes for clinical practice, genetic counselling and personalized care, and present our recommendations for the use of NGS-based tests in routine nephrology practice.

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“…8 WDR19 mutations have been found in human patients with certain ciliopathies, including Sensenbrenner and Jeune syndromes. 9 The Wdr19 mouse line used in this study was created using random insertional mutagenesis (data not shown). Heterozygous mice are viable and do not exhibit obvious defects; homozygous Wdr19 mutants are embryonic lethal at about embryonic day 10.5 (E10.5) exhibiting defects in neural tube closure and brain development.…”

mentioning

confidence: 99%