Homozygous variants in <i>KIAA1549</i>, encoding a ciliary protein, are associated with autosomal recessive retinitis pigmentosa

Bruijn, Suzanne E. de; Verbakel, Sanne K; Vrieze, Erik de; Kremer, Hannie; Cremers, Frans P.M.; Hoyng, Carel B.; Born, L. Ingeborgh van den; Roosing, Susanne

doi:10.1136/jmedgenet-2018-105364

Cited by 14 publications

(7 citation statements)

References 22 publications

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“…Nevertheless, the downregulation of KIAA1549 in the mouse retina of the Pomt 1 cKO mice evidenced here, strongly suggests that O -mannosylation is important for its proper transportation and/or stability. Our data also indicate that selective expression of KIAA1549 occurs in photoreceptor cells of the retina and suggest a possible role of this protein in the formation and functioning of the synapse between photoreceptors and their postsynaptic cells (Figure ), due to the staining that we and others observed in the synaptic space, but this warrants further studies.…”

Section: Discussionsupporting

confidence: 68%

“…Of note, homozygous mutations in the KIAA 1549 gene cause retinitis pigmentosa-86 (RP86, MIM: # 618613), which courses with clinical symptoms including atrophy of the outer retinal layers with preservation of the photoreceptors in the fovea, and degenerated photoreceptor outer segments . Therefore, here we hypothesize that the shortening of the OS/IS segments of the photoreceptors observed in the retina of Pomt 1 cKO mice is not directly related to α-DG glycosylation, but occurs due to the loss of KIAA1549 (Figure ) at the cilium, with a concomitant change in the BBSome complex as described above.…”

Section: Discussionmentioning

confidence: 87%

“…One of these is KIAA1549 (Uniprot ID: D3YTS3), which was found in lower levels in the retina of Pomt 1 cKO mice (Figure C). Recently the location of this protein was shown at the connecting cilium of photoreceptor cells and in the OPL of the mouse retina . Indeed, using immunofluorescence staining, KIAA1549 was observed mainly in the OPL, and also in the OS/IS of photoreceptors in retinal sections of control mice (Figure ).…”

Section: Resultsmentioning

confidence: 92%

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Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors

et al. 2021

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Mutations in the POMT1 gene, encoding a protein O-mannosyltransferase essential for α-dystroglycan (α-DG) glycosylation, are frequently observed in a group of rare congenital muscular dystrophies, collectively known as dystroglycanopathies. However, it is hitherto unclear whether the effects seen in affected patients can be fully ascribed to α-DG hypoglycosylation. To study this, here we used comparative mass spectrometry-based proteomics and immunofluorescence microscopy and investigated the changes in the retina of mice in which Pomt1 is specifically knocked out in photoreceptor cells. Our results demonstrate significant proteomic changes and associated structural alteration in photoreceptor cells of Pomt1 cKO mice. In addition to the effects related to impaired α-DG O-mannosylation, we observed morphological alterations in the outer segment that are associated with dysregulation of a relatively understudied POMT1 substrate (KIAA1549), BBSome proteins, and retinal stress markers. In conclusion, our study provides new hypotheses to explain the phenotypic changes that are observed in the retina of patients with dystroglycanopathies.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 87%

Section: Resultsmentioning

confidence: 92%

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Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors

et al. 2021

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“… 27 For KIAA1549 , there is a single report of two families. 28 For GDF6 , there is a single report of a patient with Leber Congenital Amaurosis, and in this case, both parents showed electroretinography (ERG) abnormalities. 29 Similarly, for CCT2 , there is a single report of Leber Congenital Amaurosis.…”

Section: Discussionmentioning

confidence: 90%

“…Implication of AHR in retinal disease comes from a report of a single family 27. For KIAA1549 , there is a single report of two families 28. For GDF6 , there is a single report of a patient with Leber Congenital Amaurosis, and in this case, both parents showed electroretinography (ERG) abnormalities 29.…”

Section: Discussionmentioning

confidence: 99%

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

et al. 2022

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BackgroundLarge databases permit quantitative description of genes in terms of intolerance to loss of function (‘haploinsufficiency’) and prevalence of missense variants. We explored these parameters in inherited retinal disease (IRD) genes.MethodsIRD genes (from the ‘RetNet’ resource) were classified by probability of loss of function intolerance (pLI) using online Genome Aggregation Database (gnomAD) and DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) databases. Genes were identified having pLI ≥0.9 together with one or both of the following: upper bound of CI <0.35 for observed to expected (o/e) ratio of loss of function variants in the gnomAD resource; haploinsufficiency score <10 in the DECIPHER resource. IRD genes in which missense variants appeared under-represented or over-represented (Z score for o/e ratio of <−2.99 or >2.99, respectively) were also identified. The genes were evaluated in the gene ontology Protein Analysis THrough Evolutionary Relationships (PANTHER) resource.ResultsOf 280 analysed genes, 39 (13.9%) were predicted loss of function intolerant. A greater proportion of X-linked than autosomal IRD genes fulfilled these criteria, as expected. Most autosomal genes were associated with dominant disease. PANTHER analysis showed >100 fold enrichment of spliceosome tri-snRNP complex assembly. Most encoded proteins were longer than the median length in the UniProt database. Fourteen genes (11 of which were in the ‘haploinsufficient’ group) showed under-representation of missense variants. Six genes (SAMD11, ALMS1, WFS1, RP1L1, KCNV2, ADAMTS18) showed over-representation of missense variants.ConclusionA minority of IRD-associated genes appear to be ‘haploinsufficient’. Over-representation of spliceosome pathways was observed. When interpreting genetic tests, variants found in genes with over-representation of missense variants should be interpreted with caution.

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The Retinitis Pigmentosa Genes

Chen

Zhao

2021

Essentials in Ophthalmology

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Homozygous variants in KIAA1549, encoding a ciliary protein, are associated with autosomal recessive retinitis pigmentosa

Abstract: In conclusion, our results underscore the causality of segregating variants in for autosomal recessive RP. Moreover, our data indicate that KIAA1549 plays a role in photoreceptor function.

Cited by 14 publications

References 22 publications

Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors

Retinal Proteomics of a Mouse Model of Dystroglycanopathies Reveals Molecular Alterations in Photoreceptors

Exploring the mutational landscape of genes associated with inherited retinal disease using large genomic datasets: identifying loss of function intolerance and outlying propensities for missense changes

The Retinitis Pigmentosa Genes

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