Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy

Cogné, Benjamin; Latypova, Xénia; Senaratne, Lokuliyanage Dona Samudita; Martin, Ludovic; Koboldt, Daniel C.; Kellaris, Georgios; Fievet, Lorraine; Meur, Guylène Le; Caldari, Dominique; Debray, Dominique; Nizon, Mathilde; Frengen, Eirik; Bowne, Sara J.; Buckley, R.; Aberdein, Danielle; Alves, Paulo C.; Barsh, Gregory S.; Bellone, Rebecca R.; Bergström, Tomas F.; Boyko, Adam R.; Brockman, Jeffrey A.; Casal, Margret L.; Castelhano, Marta G.; Distl, O.; Dodman, Nicholas H.; Ellinwood, N. Matthew; Fogle, Jonathan E.; Forman, Oliver P.; Garrick, Dorian J.; Ginns, Edward I.; Häggström, Jens; Harvey, Robert J.; Hasegawa, Daisuke; Haase, Bianca; Helps, Christopher R; Hernández, Isabel; Hytönen, Marjo K.; Kaukonen, Maria; Kaelin, Christopher B.; Kosho, Tomoki; Leclerc, Emilie; Lear, Teri L.; Leeb, Tosso; Li, Ronald H. L.; Lohi, Hannes; Longeri, M.; Magnuson, Mark A.; Malík, Richard; Mane, Shrinivas P.; Munday, John S.; Murphy, William J.; Pedersen, Niels C; Rothschild, Max F.; Rusbridge, Clare; Shapiro, Beth; Stern, Joshua A.; Swanson, William F.; Terio, Karen A.; Todhunter, Rory J.; Warren, Wesley C.; Wilcox, Elizabeth A.; Wildschutte, Julia H; Yu, Yoshihiko; Cadena, Elizabeth L.; Daiger, Stephen P.; Bujakowska, Kinga; Pierce, Eric A.; Gorin, Michael B.; Katsanis, Nicholas; Bézieau, Stéphane; Petersen‐Jones, Simon M.; Occelli, Laurence M.; Lyons, Leslie A.; Legeai-Mallet, Laurence; Sullivan, Lori S.; Davis, Erica E.; Isidor, Bertrand

doi:10.1016/j.ajhg.2020.04.005

Cited by 36 publications

(24 citation statements)

References 41 publications

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“…Forty-four known variants were identified in the WES cohort. All variants for coat colors and diseases known to be present in the ten cats were identified, including the alleles in the loci for Agouti ( ASIP - a 48 ), Brown (TYRP1 – b) 49 , Color (TYR – c s ) 50 , Dense (MLPH) 51 , Longhair ( FGF5 ) 52 , Lykoi ( HR ) 53 , Bengal ( KIF3B ) 54 and Persian progressive retinal degeneration ( AIPL1 ) 27 , hydrocephalus ( GDF7 ) 55 , and others ( Supplementary Data 5) . The cats had various known mutations affecting cat blood type.…”

Section: Resultsmentioning

confidence: 99%

A domestic cat whole exome sequencing resource for trait discovery

Rodney

Buckley

Fulton

et al. 2020

Preprint

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Over 94 million domestic cats are considered pets, who, as our companions, are also susceptible to cancers, common and rare diseases. Whole exome sequencing (WES) is a cost-effective strategy to study their putative disease-causing variants. Presented is ~35.8 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. WES was conducted on 41 cats from various breeds with known and unknown diseases and traits, including 10 cats with prior whole genome sequence (WGS) data available, to test WES capture probe performance. A WES and WGS comparison was completed to understand variant discovery capability of each platform. At ~80x exome coverage, the percent of on-target base coverage >20x was 96.4% with an average of 10.4% off-target. For variant discovery, greater than 98% of WGS SNPs were also discovered by WES. Platform specific variants were mainly restricted to a small number of sex chromosome and olfactory receptor genes. Within the 41 cats with ~31 diseases and normal traits, 45 previously known disease or trait causal variants were observed, such as Persian progressive retinal degeneration and hydrocephalus. Novel candidate variants for polycystic kidney disease and atrichia in the Peterbald breed were also identified as well as a new cat patient with a known variant for cystinuria. These results show the discovery potential of deep exome sequencing to validate existing disease gene models and identify novel gene candidate alleles for many common and rare diseases in cats.

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Section: Resultsmentioning

confidence: 99%

A domestic cat whole exome sequencing resource for trait discovery

Rodney

Buckley

Fulton

et al. 2020

Preprint

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“…The development of the 99 Lives cat genome sequencing database and improved assembly and annotation of the cat have led to vastly improved variation identification for cats and the ability to define candidate genes and variants based on cat phenotypes (Buckley et al 2020a;Buckley et al 2020b;Cogne et al 2020;Jaffey et al 2019;Mauler et al 2017;Pettersen et al 2021;Yu et al 2020). As the cat used for the reference genome has the ticked phenotype of interest, and because this variant is autosomal dominant and a ticked cat, such as the reference cat, can be heterozygous, the wt allele (non-ticked) may or may not be the reference allele in the cat genome assembly.…”

Section: Discussionmentioning

confidence: 99%

“…Two phenotypically ticked cats were known to be heterozygous (obligate heterozygous) for the ticked allele as they were produced by a breeding of a tabby cat (Bengal) mated with a pedigreed ticked Somali (Fig. 1g,h; Cogne et al 2020). The cats used in each filtering step are presented in Table 1.…”

Section: Variant Filteringmentioning

confidence: 99%

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)

2021

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Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (T a ; a.k.a. ticked), mackerel (T m ; a.k.a. striped) and blotched (t b ; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby -Abyssinian (T a ; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele (s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine-rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B.

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“…Young adults have OS defects, primarily affecting the rods, which progress to rod degeneration and eventual cone OS defects. KIF3B encodes a kinesin motor involved in transport through the cilium and mutations in KIF3B have recently been associated with a ciliopathy that presents with RP [ 159 ]. kif3b mutant zebrafish have rapid rod degeneration and delayed OS genesis, but cones appear normal [ 160 , 161 ].…”

Section: Zebrafish Models Of Photoreceptor Diseasementioning

confidence: 99%

Zebrafish Models of Photoreceptor Dysfunction and Degeneration

2021

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Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome.

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Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy

Cited by 36 publications

References 41 publications

A domestic cat whole exome sequencing resource for trait discovery

A domestic cat whole exome sequencing resource for trait discovery

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus)

Zebrafish Models of Photoreceptor Dysfunction and Degeneration

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