Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

Rivas, Lucía; Blanco, Óscar; Torreira, Cristina; Repáraz, Alfredo; Melcón, Cristina; Amado, Alfonso

doi:10.4067/s0370-41062017000400014

Cited by 8 publications

(4 citation statements)

References 14 publications

(40 reference statements)

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“…The CASK protein is highly expressed in the central nervous system and engages in brain development and synaptic function. Intriguingly, the function of the CASK gene varies with the periods of brain development (Hsueh, 2006;Rivas et al, 2017). CASK mutations lead to interference of the neuronal migration and consequent neurodevelopmental disorder.…”

Section: Discussionmentioning

confidence: 99%

Case report: A novel CASK mutation in a Chinese female child with microcephaly with pontine and cerebellar hypoplasia

et al. 2022

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Objective: Microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a rare X-linked dominant genetic disease, and most MICPCHs are ascribed to CASK mutations, while few are revealed in Chinese patients. This study aims to identify the pathogenic mutation in a Chinese proband with MICPCH.Methods: A 3-year-old female Chinese proband with MICPCH and her parents were included. Clinical data were collected from the medical records and recalled by the proband’s mother. Whole genome sequencing and Sanger sequencing were used to find the pathogenic mutation of MICPCH.Results: The proband presented with postnatal progressive microcephaly, cerebellar hypoplasia, intellectual disability, motor and language development retardation and limb hypertonia. Genetic analysis indicated that there was a novel compound heterozygote nonsynonymous mutation, c.755T>C(p.Leu252Pro) in exon8 of CASK gene in the proband, but not in her parents. This CASK mutation has not been reported in other databases.Conclusion: This study broadens the mutation spectrum of the CASK gene and is of great value for precise prenatal diagnosis and genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Case report: A novel CASK mutation in a Chinese female child with microcephaly with pontine and cerebellar hypoplasia

et al. 2022

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“…However, some variants are not associated with clinical phenotypes on the database (12/37 in frameshift; 58/227 in missense; and 15/44 in nonsense). To evaluate the association between the mutations of the CASK gene and clinical phenotypes, we investigated 49 reports describing 197 patients with CASK -related disorders [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 46 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ] and classified the cases based on the genders and phenotypes ( Table 2 ).…”

Section: Genetics Of Cask -Related Disordersmentioning

confidence: 99%

Diverse Clinical Phenotypes of CASK-Related Disorders and Multiple Functional Domains of CASK Protein

Mori,

Zhou,

Tabuchi

2023

Genes

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CASK-related disorders are a form of rare X-linked neurological diseases and most of the patients are females. They are characterized by several symptoms, including microcephaly with pontine and cerebellar hypoplasia (MICPCH), epilepsy, congenital nystagmus, and neurodevelopmental disorders. Whole-genome sequencing has identified various mutations, including nonsense and missense mutations, from patients with CASK-related disorders, revealing correlations between specific mutations and clinical phenotypes. Notably, missense mutations associated with epilepsy and intellectual disability were found throughout the whole region of the CASK protein, while missense mutations related to microcephaly and MICPCH were restricted in certain domains. To investigate the pathophysiology of CASK-related disorders, research groups have employed diverse methods, including the generation of CASK knockout mice and the supplementation of CASK to rescue the phenotypes. These approaches have yielded valuable insights into the identification of functional domains of the CASK protein associated with a specific phenotype. Additionally, recent advancements in the AI-based prediction of protein structure, such as AlphaFold2, and the application of genome-editing techniques to generate CASK mutant mice carrying missense mutations from patients with CASK-related disorders, allow us to understand the pathophysiology of CASK-related disorders in more depth and to develop novel therapeutic methods for the fundamental treatment of CASK-related disorders.

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“…At the high end of the range is microcephaly with pontine-cerebellar hypoplasia (MICPCH, MIM# 300749; https://omim.org/entry/300749 , last accessed 9 February 2023), a congenital disorder that causes severe psychomotor delay, often with early-onset, hard-to-control epilepsy, optic nerve/retinal abnormalities, and/or short stature. These patients have de novo germline CASK mutations, and most but not all are heterozygous females [ 47 , 49 , 55 – 57 , 71 , 80 , 100 , 103 , 104 , 112 , 113 , 120 , 128 , 129 , 149 , 153 , 160 ]. In other cases, the phenotypes do not fit neatly into either category, including autism spectrum disorder (ASD) without ID in males or females [ 10 , 64 , 139 ], progressive microcephaly without cerebellar/pontine abnormalities [ 24 ], or focal cortical dysplasia in a female with a large somatic CASK -mutant clone [ 83 ].…”

Section: Introductionmentioning

confidence: 99%

Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery

Tello,

Jiang,

Zohar

et al. 2023

Neural Dev

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Background CASK-related neurodevelopmental disorders are untreatable. Affected children show variable severity, with microcephaly, intellectual disability (ID), and short stature as common features. X-linked human CASK shows dosage sensitivity with haploinsufficiency in females. CASK protein has multiple domains, binding partners, and proposed functions at synapses and in the nucleus. Human and Drosophila CASK show high amino-acid-sequence similarity in all functional domains. Flies homozygous for a hypomorphic CASK mutation (∆18) have motor and cognitive deficits. A Drosophila genetic model of CASK-related disorders could have great scientific and translational value. Methods We assessed the effects of CASK loss of function on morphological phenotypes in Drosophila using established genetic, histological, and primary neuronal culture approaches. NeuronMetrics software was used to quantify neurite-arbor morphology. Standard nonparametric statistics methods were supplemented by linear mixed effects modeling in some cases. Microfluidic devices of varied dimensions were fabricated and numerous fluid-flow parameters were used to induce oscillatory stress fields on CNS tissue. Dissociation into viable neurons and neurite outgrowth in vitro were assessed. Results We demonstrated that ∆18 homozygous flies have small brains, small heads, and short bodies. When neurons from developing CASK-mutant CNS were cultured in vitro, they grew small neurite arbors with a distinctive, quantifiable “bushy” morphology that was significantly rescued by transgenic CASK+. As in humans, the bushy phenotype showed dosage-sensitive severity. To overcome the limitations of manual tissue trituration for neuronal culture, we optimized the design and operation of a microfluidic system for standardized, automated dissociation of CNS tissue into individual viable neurons. Neurons from CASK-mutant CNS dissociated in the microfluidic system recapitulate the bushy morphology. Moreover, for any given genotype, device-dissociated neurons grew larger arbors than did manually dissociated neurons. This automated dissociation method is also effective for rodent CNS. Conclusions These biological and engineering advances set the stage for drug discovery using the Drosophila model of CASK-related disorders. The bushy phenotype provides a cell-based assay for compound screening. Nearly a dozen genes encoding CASK-binding proteins or transcriptional targets also have brain-development mutant phenotypes, including ID. Hence, drugs that improve CASK phenotypes might also benefit children with disorders due to mutant CASK partners.

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Hipoplasia pontocerebelosa secundaria a deleción en el gen CASK: Caso clínico

Cited by 8 publications

References 14 publications

Case report: A novel CASK mutation in a Chinese female child with microcephaly with pontine and cerebellar hypoplasia

Case report: A novel CASK mutation in a Chinese female child with microcephaly with pontine and cerebellar hypoplasia

Diverse Clinical Phenotypes of CASK-Related Disorders and Multiple Functional Domains of CASK Protein

Drosophila CASK regulates brain size and neuronal morphogenesis, providing a genetic model of postnatal microcephaly suitable for drug discovery

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