Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Otto, Edgar A.; Hurd, Toby W.; Airik, Rannar; Chaki, Moumita; Zhou, Weibin; Stoetzel, Corinne; Patil, Suresh B.; Levy, Shawn; Ghosh, Amiya K.; Murga‐Zamalloa, Carlos; Reeuwijk, Jeroen van; Letteboer, Stef J.F.; Sang, Liyun; Giles, Rachel; Liu, Qin; Coene, Karlien L M; Estrada-Cuzcano, Alejandro; Collin, Rob W.J.; McLaughlin, Heather; Held, Susanne; Kasanuki, J. M.; Ramaswami, Gokul; Conte, Jinny; López, Irma; Washburn, Joseph; MacDonald, James W.; Hu, Jinghua; Yamashita, Yukiko; Maher, Eamonn R.; Guay‐Woodford, Lisa M.; Neumann, Hartmut P. H.; Obermüller, Nicholas; Koenekoop, Robert K.; Bergmann, Carsten; Bei, Xiaoshu; Lewis, Richard A.; Katsanis, Nicholas; Lopes, Vanda S.; Williams, David S.; Lyons, Robert H.; Dang, Chi V.; Brito, Daniela A.; Bettencourt-Dias, Mónica; Zhang, Xinmin; Cavalcoli, James D.; Nürnberg, Gudrun; Nürnberg, Peter; Pierce, Eric A.; Jackson, Peter K.; Antignac, Corinne; Saunier, Sophie; Roepman, Ronald; Dollfus, Hélène; Khanna, Hemant; Hildebrandt, Friedhelm

doi:10.1038/ng.662

Cited by 292 publications

(306 citation statements)

References 41 publications

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“…We added 35 ciliary genes from chromosomal regions identified by homozygosity mapping (Human CNV370-Quadv3 Illumina bead array, Illumina, San Diego, CA, USA) in one consanguineous family. Furthermore, we added candidate genes based on the literature on retinal and renal ciliary genes 16 (see Supplementary Table S1 for a list of all included genes).…”

Section: A Targeted Ngs Arraymentioning

confidence: 99%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

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Section: A Targeted Ngs Arraymentioning

confidence: 99%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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“…In consanguineous families, we combined WES with HM, as established previously (40,41). Genetic regions of homozygosity were plotted across the genome ( Figure 1A) (42,43). Exome capture was performed with the Agilent SureSelect V5 Enrichment Capture Kit.…”

Section: Methodsmentioning

confidence: 99%

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Lovric¹,

Gonçalves²,

Gee³

et al. 2017

Journal of Clinical Investigation

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Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of diseaseassociated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

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“…For example, while the studies described above have revealed the identity of cilia and centrosomes components, we still do not know how most of these components dynamically localize, interact, and function at the molecular, cellular, and organismal level. Likewise, the causative gene in families with ciliopathies is unknown in most cases, suggesting that additional genes expected to be associated with cilia or centrosomes remain to be identified (Otto et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods

et al. 2011

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Centrosomes in animal cells are dynamic organelles with a proteinaceous matrix of pericentriolar material assembled around a pair of centrioles. They organize the microtubule cytoskeleton and the mitotic spindle apparatus. Mature centrioles are essential for biogenesis of primary cilia that mediate key signalling events. Despite recent advances, the molecular basis for the plethora of processes coordinated by centrosomes is not fully understood. We have combined protein identification and localization, using PCP-SILAC mass spectrometry, BAC transgeneOmics, and antibodies to define the constituents of human centrosomes. From a background of non-specific proteins, we distinguished 126 known and 40 candidate centrosomal proteins, of which 22 were confirmed as novel components. An antibody screen covering 4000 genes revealed an additional 113 candidates. We illustrate the power of our methods by identifying a novel set of five proteins preferentially associated with mother or daughter centrioles, comprising genes implicated in cell polarity. Pulsed labelling demonstrates a remarkable variation in the stability of centrosomal protein complexes. These spatiotemporal proteomics data provide leads to the further functional characterization of centrosomal proteins.

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Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal-renal ciliopathy

Cited by 292 publications

References 41 publications

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome: genotyping a Northern European patient cohort

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Novel asymmetrically localizing components of human centrosomes identified by complementary proteomics methods

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