• Journal of Genetic Medicine
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• v.18 no.1
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• pp.64-69
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• 2021

Primary cilium has a signal transduction function that is essential for brain development, and also determines cell polarity and acts as a mediator for important signaling systems, especially the Sonic Hedgehog (SHH) pathway. TBC1D32 is a ciliary protein, implicated in SHH signaling. Biallelic mutations in the TBC1D32 gene causes a kind of ciliopathy, heterogeneous developmental or degenerative disorders that affect multiple organs, including the brain. Here we report a boy who carried compound heterozygous variants in TBC1D32. The patient showed hypotonia, respiratory difficulty, and multiple anomalies at his birth. He was diagnosed with congenital hypopituitarism and treated with T4, hydrocortisone, and growth hormone. Despite the hormonal replacement, the patient needed long-term respiratory support with tracheostomy and nutritional support with a feeding tube. His developmental milestones were severely retarded. Hydrocephalus and strabismus developed and both required surgery, during the outpatient follow-up. Whole-exome sequencing indicated compound heterozygous variants, c.2200C>T (p.Arg734^*) and c.156-1G>T, in TBC1D32 gene. This is the first Korean case of TBC1D32-related ciliopathy and we reported detailed and sequential clinical features. This case demonstrated the utility of whole-exome sequencing and provided valuable clinical data on ultra-rare disease.

• BMB Reports
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• v.48 no.12
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• pp.647-654
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• 2015

Energy homeostasis in our body system is maintained by balancing the intake and expenditure of energy. Excessive accumulation of fat by disrupting the balance system causes overweight and obesity, which are increasingly becoming global health concerns. Understanding the pathogenesis of obesity focused on studying the genes related to familial types of obesity. Recently, a rare human genetic disorder, ciliopathy, links the role for genes regulating structure and function of a cellular organelle, the primary cilium, to metabolic disorder, obesity and type II diabetes. Primary cilia are microtubule based hair-like membranous structures, lacking motility and functions such as sensing the environmental cues, and transducing extracellular signals within the cells. Interestingly, the subclass of ciliopathies, such as Bardet-Biedle and Alström syndrome, manifest obesity and type II diabetes in human and mouse model systems. Moreover, studies on genetic mouse model system indicate that more ciliary genes affect energy homeostasis through multiple regulatory steps such as central and peripheral actions of leptin and insulin. In this review, we discuss the latest findings in primary cilia and metabolic disorders, and propose the possible interaction between primary cilia and the leptin and insulin signal pathways which might enhance our understanding of the unambiguous link of a cell's antenna to obesity and type II diabetes.

• Childhood Kidney Diseases
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• v.19 no.1
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• pp.23-30
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• 2015

NPHP is the most common monogenic cause of CKD in children or adolescents. Extra-renal symptoms often accompany, therefore examination of retina, hearing, and skeleton is necessary in patients with CKD with insidious onset. Genes involved in NPHP-RC are mostly related in primary cilia. While genetic diagnosis is necessary for definitive diagnosis, there is no curative treatment.

• Biomolecules & Therapeutics
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• v.27 no.4
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• pp.337-341
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• 2019

Primary cilia and autophagy are two distinct nutrient-sensing machineries required for maintaining intracellular energy homeostasis, either via signal transduction or recycling of macromolecules from cargo breakdown, respectively. Potential correlations between primary cilia and autophagy have been recently suggested and their relationship may increase our understanding of the pathogenesis of human diseases, including ciliopathies and cancer. In this review, we cover the current issues concerning the bidirectional interaction between primary cilia and autophagy and discuss its role in cancer with cilia defect.

• Molecules and Cells
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• v.40 no.6
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• pp.401-409
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• 2017

The primary cilium is a non-motile microtubule-based organelle that protrudes from the surface of most human cells and works as a cellular antenna to accept extracellular signals. Primary cilia assemble from the basal body during the resting stage ($G_0$ phase) and simultaneously disassemble with cell cycle re-entry. Defective control of assembly or disassembly causes diverse human diseases including ciliopathy and cancer. To identify the effective compounds for studying primary cilium disassembly, we have screened 297 natural compounds and identified 18 and 17 primary cilium assembly and disassembly inhibitors, respectively. Among them, the application of KY-0120, identified as Brefeldin A, disturbed Dvl2-Plk1-mediated cilium disassembly via repression of the interaction of $CK1{\varepsilon}-Dvl2$ and the expression of Plk1 mRNA. Therefore, our study may suggest useful compounds for studying the cellular mechanism of primary cilium disassembly to prevent ciliopathy and cancer.

• Molecules and Cells
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• v.40 no.4
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• pp.243-253
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• 2017

Eukaryotic cilia are organelles that project from the surface of cells to fulfill motility and sensory functions. In vertebrates, the functions of both motile and immotile cilia are critical for embryonic development and adult tissue homeostasis. Importantly, a multitude of human diseases is caused by abnormal cilia biogenesis and functions which rely on the compartmentalization of the cilium and the maintenance of its protein composition. The transition zone (TZ) is a specialized ciliary domain present at the base of the cilium and is part of a gate that controls protein entry and exit from this organelle. The relevance of the TZ is highlighted by the fact that several of its components are coded by ciliopathy genes. Here we review recent developments in the study of TZ proteomes, the mapping of individual components to the TZ structure and the establishment of the TZ as a lipid gate.

• BMB Reports
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• v.45 no.8
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• pp.427-432
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• 2012

Primary cilia, single hair-like appendage on the surface of the most mammalian cells, were once considered to be vestigial cellular organelles for a past century because of their tiny structure and unknown function. Although they lack ancestral motility function of cilia or flagella, they share common ground with multiciliated motile cilia and flagella on internal structure such as microtubule based nine outer doublets nucleated from the base of mother centrioles called basal body. Making cilia, ciliogenesis, in cells depends on the cell cycle stage due to reuse of centrioles for cell division forming mitotic spindle pole (M phase) and assembling cilia from basal body (starting G1 phase and maintaining most of interphase). Ciliary assembly required two conflicting processes such as assembly and disassembly and balance between these two processes determines the length of cilia. Both process required highly conserved transport system to supply needed substance to grow tip of cilia and bring ciliary turnover product back to the base of cilia using motor protein, kinesin and dynein, and transport protein complex, IFT particles. Disruption of ciliary structure or function causes multiple human disorder called ciliopathies affecting disease of diverse ciliated tissues ranging from eye, kidney, respiratory tract and brain. Recent explosion of research on the primary cilia and their involvement on animal development and disease attracts scientific interest on how extensively the function of cilia related to specific cell physiology and signaling pathway. In this review, I introduce general features of primary cilia and recent progress in understanding of the ciliary length control and signaling pathways transduced through primary cilia in vertebrates.

• Journal of Genetic Medicine
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• v.11 no.1
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• pp.31-35
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• 2014

Bardet-Biedl syndrome (BBS) is a rare ciliopathy generally inherited with an autosomal recessive pattern. BBS is characterized by 6 primary features namely retinal dystrophy, obesity, postaxial polydactyly, renal dysfunction, learning difficulties, and hypogonadism and a wide range of secondary features. To date, mutations in 16 genes have been identified as causative factors for BBS. Among them, the BBS1 and BBS10 genes are major disease-causing genes, and each of these gene mutations presents in more than 20% of all BBS patients. Genotype-phenotype correlations have not been observed in BBS, and there can be phenotypic overlap between BBS and other ciliopathies. In Korea, no molecular, genetically confirmed case of BBS has been reported to date. Herein, we describe the case of the first Korean siblings with BBS resulting from 2 BBS10 gene mutations who showed typical clinical phenotypes, including retinal dystrophy, obesity, intellectual disability, cystic tubular disease, and postaxial polydactyly.

• Molecules and Cells
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• v.45 no.4
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• pp.169-176
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• 2022

A primary cilium, a hair-like protrusion of the plasma membrane, is a pivotal organelle for sensing external environmental signals and transducing intracellular signaling. An interesting linkage between cilia and obesity has been revealed by studies of the human genetic ciliopathies Bardet-Biedl syndrome and Alström syndrome, in which obesity is a principal manifestation. Mouse models of cell type-specific cilia dysgenesis have subsequently demonstrated that ciliary defects restricted to specific hypothalamic neurons are sufficient to induce obesity and hyperphagia. A potential mechanism underlying hypothalamic neuron cilia-related obesity is impaired ciliary localization of G protein-coupled receptors involved in the regulation of appetite and energy metabolism. A well-studied example of this is melanocortin 4 receptor (MC4R), mutations in which are the most common cause of human monogenic obesity. In the paraventricular hypothalamus neurons, a blockade of ciliary trafficking of MC4R as well as its downstream ciliary signaling leads to hyperphagia and weight gain. Another potential mechanism is reduced leptin signaling in hypothalamic neurons with defective cilia. Leptin receptors traffic to the periciliary area upon leptin stimulation. Moreover, defects in cilia formation hamper leptin signaling and actions in both developing and differentiated hypothalamic neurons. The list of obesity-linked ciliary proteins is expending and this supports a tight association between cilia and obesity. This article provides a brief review on the mechanism of how ciliary defects in hypothalamic neurons facilitate obesity.

• Journal of Genetic Medicine
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• v.17 no.1
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• pp.39-42
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• 2020

The Senior-Loken syndrome was first described in 1961 as an oculo-renal disease consisting of familial juvenile nephronophthisis and Leber congenital amaurosis. It is a rare autosomal recessive disorder with a prevalence of 1:1,000,000 caused by mutations in nine genes (NPHP 1-8 and NPHP 10). Ocular manifestations (e.g., photophobia, nystagmus, and extreme hyperopia) occur within the first few years of life while renal manifestations (e.g., formation of multiple cysts impairing kidney function and end-stage renal disease) appear in late childhood to adolescence. Here, we report a case of a Filipino male presenting with rotatory nystagmus and progressive deterioration of vision since childhood. He had congenital amaurosis and juvenile nephronophthisis that progressed to end stage renal disease by age 19. All laboratory and imaging findings were consistent with chronic kidney disease. Molecular genetic testing of ciliopathy-related genes was performed revealing a homozygous mutation in exon 11 of the IQCB1/NPHP5 gene, c.1090C>T (p.Arg364^⁎). This sequence change created a premature translational stop signal resulting in a truncated protein product, nephrocystin-5 and its consequent loss of function. His symptoms eventually improved with initiation dialysis. The prognosis of Senior-Loken syndrome remains dismal and a high index of suspicion, early diagnosis and timely intervention of renal complications are warranted.