Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability

Kim, Cheol‐Hee; Lee, Yu-Ri; Thomas, Mervyn G; Roychaudhury, Arkaprava; Skinner, Cindy; Maconachie, Gail; Crosier, Moira; Horak, Holli A.; Constantinescu, Cris S.; Choi, Tae‐Ik; Kyung, Jae-Jun; Wang, Tao; Ku, Bonsu; Chodirker, Bernard N.; Hammer, Michael F.; Gottlob, Irène; Norton, William; Chudley, Albert E.; Schwartz, Charles E.

doi:10.21203/rs.3.rs-2683050/v1

Cited by 3 publications

(3 citation statements)

References 51 publications

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“…Similar upregulation was seen in a knock-in RBM20 mouse model (Rbm20 S637A ) where phosphorylation was impaired 33 . While in our hands the srpk3-null 5-dpf zebrafish appeared normal with almost unaffected fiber structure, at the time of submission an adult KO model was shown to present agenesis of cerebellar structures and abnormal behavior 34 , suggesting srpk3 may also be involved in neural development.…”

Section: Discussioncontrasting

confidence: 47%

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Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Töpf,

Cox,

Zaharieva

et al. 2024

Nat Genet

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In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.

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Section: Discussioncontrasting

confidence: 47%

“…59). In fact, SRPK3 has previously been suggested as a causative gene in patients with X-linked spinocerebellar ataxia 60 and intellectual disability 34,61 . Notably, it has been proposed that abnormal SRPK-mediated phosphorylation of an E3 ubiquitin ligase might disrupt neurodevelopmental regulation 45,56 .…”

Section: Articlementioning

confidence: 99%

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Töpf,

Cox,

Zaharieva

et al. 2024

Nat Genet

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show abstract

“… 18 A zebrafish knockout study in which Srpk3 −/− fish were raised to adulthood has recently revealed SRPK3 to be a compelling candidate gene for X‐linked intellectual disability. 19 The impact of its deletion in our patient and two others is unclear, however, due to the early mortality reported in CADDS. 6 , 8 …”

Section: Discussionmentioning

confidence: 72%

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review

Heath,

Pandithan,

Pitt

et al. 2023

JIMD Reports

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Contiguous ABCD1/ DXS1357E deletion syndrome (CADDS) is a rare deletion syndrome involving two contiguous genes on Xq28, ABCD1 and BCAP31 (formerly known as DXS1357E). Only nine individuals with this diagnosis have been reported in the medical literature to date. Intragenic loss‐of‐function variants in BCAP31 cause the deafness, dystonia, and cerebral hypomyelination syndrome (DDCH). Isolated pathogenic intragenic variants in ABCD1 are associated with the most common peroxisomal disorder, X‐linked adrenoleukodystrophy (X‐ALD), a single transporter deficiency, which in its more severe cerebral form is characterised by childhood‐onset neurodegeneration and high levels of very‐long‐chain fatty acids (VLCFA). While increased VLCFA levels also feature in CADDS, the few patients described to date all presented as neonates with a severe phenotype. Here we report a tenth individual with CADDS, a male infant with dysmorphic facial features who was diagnosed through ultra‐rapid whole genome sequencing (WGS) in the setting of persistent cholestatic liver disease, sensorineural hearing loss, hypotonia and growth failure and developmental delay. Biochemical studies showed elevated VLCFA and mildly reduced plasmalogens. He died at 7 months having developed pancreatic exocrine deficiency and interstitial lung disease, two features we propose to be possible extensions to the CADDS phenotype. We also review the genetic, phenotypic, and biochemical features in previously reported individuals with CADDS.

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Impairments of cerebellar structure and function in a zebrafish KO of neuropsychiatric risk gene znf536

Kim,

Roychaudhury,

Kim

et al. 2024

Transl Psychiatry

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Genetic variants in ZNF536 contribute to the risk for neuropsychiatric disorders such as schizophrenia, autism, and others. The role of this putative transcriptional repressor in brain development and function is, however, largely unknown. We generated znf536 knockout (KO) zebrafish and studied their behavior, brain anatomy, and brain function. Larval KO zebrafish showed a reduced ability to compete for food, resulting in decreased total body length and size. This phenotype can be rescued by segregating the homozygous KO larvae from their wild-type and heterozygous siblings, enabling studies of adult homozygous KO animals. In adult KO zebrafish, we observed significant reductions in anxiety-like behavior and social interaction. These znf536 KO zebrafish have decreased cerebellar volume, corresponding to decreased populations of specific neuronal cells, especially in the valvular cerebelli (Va). Finally, using a Tg[mbp:mgfp] line, we identified a previously undetected myelin structure located bilaterally within the Va, which also displayed a reduction in volume and disorganization in KO zebrafish. These findings indicate an important role for ZNF536 in brain development and implicate the cerebellum in the pathophysiology of neuropsychiatric disorders.

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Eye movement defects in KO zebrafish reveals SRPK3 as a causative gene for an X-linked intellectual disability

Cited by 3 publications

References 51 publications

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

Interstitial lung disease and pancreatic exocrine insufficiency in CADDS: Phenotypic expansion and literature review

Impairments of cerebellar structure and function in a zebrafish KO of neuropsychiatric risk gene znf536

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