Kashin-Beck Disease
Introduction
Section titled “Introduction”Kashin-Beck disease (KBD) is a chronic, endemic osteochondropathy primarily affecting the cartilage and bone development in children and adolescents, leading to degenerative joint disease.[1]It is characterized by the necrosis of chondrocytes in the growth plates and articular cartilage, resulting in stunted growth, joint deformities, and severe osteoarthritis.[2]The disease is predominantly found in specific geographic regions of Siberia, North Korea, and particularly in rural areas of China, where millions are at risk or affected.[3]
Biological Basis
Section titled “Biological Basis”The precise biological basis of Kashin-Beck disease is complex and believed to be multifactorial, involving a combination of genetic predispositions and environmental factors. A leading hypothesis points to chronic selenium deficiency, which can impair the function of antioxidant enzymes like glutathione peroxidase, making chondrocytes more susceptible to oxidative stress.[4] Additionally, mycotoxin contamination, specifically T-2 toxin produced by Fusarium fungi in cereal grains, is thought to play a significant role. This toxin can interfere with cartilage metabolism and cell proliferation.[5]The interaction between these nutritional deficiencies, environmental toxins, and potential genetic susceptibilities, such as variations in genes related to antioxidant defense or cartilage maintenance, is considered crucial to the disease’s pathogenesis.[6]
Clinical Relevance
Section titled “Clinical Relevance”Clinically, KBD manifests with pain, stiffness, and enlargement of the peripheral joints, particularly in the hands, feet, knees, and elbows.[7]Children often experience short stature due to impaired epiphyseal growth, and severe cases can lead to significant physical disability, making daily activities challenging. Diagnosis typically involves a combination of clinical examination, X-rays showing characteristic bone and joint changes (such as epiphyseal necrosis and widened growth plates), and sometimes blood tests to assess nutritional status. Early diagnosis is critical, as progression can be slowed or halted with interventions, although established joint damage is largely irreversible. Treatment is primarily symptomatic, focusing on pain management, physical therapy, and in advanced stages, orthopedic surgery.[8]
Social Importance
Section titled “Social Importance”Kashin-Beck disease carries significant social and economic importance, especially in the affected rural communities. The debilitating nature of the disease impacts the quality of life for individuals, limiting their ability to perform manual labor, attend school, or participate fully in community life.[9] This can lead to decreased productivity, poverty, and a heavy burden on healthcare systems. Public health efforts have focused on prevention, including selenium supplementation programs, improving dietary diversity, and educating communities on safe food storage practices to reduce mycotoxin exposure.[2] Understanding the genetic and environmental interplay is vital for developing effective screening, prevention, and treatment strategies to alleviate the suffering and socioeconomic impact of this chronic condition.[3]
Limitations
Section titled “Limitations”Research into the genetic underpinnings of kashin beck disease, while yielding valuable insights, is subject to several methodological and interpretative limitations. Acknowledging these constraints is crucial for a balanced understanding of current findings and for guiding future investigations.
Methodological and Statistical Constraints
Section titled “Methodological and Statistical Constraints”A primary limitation stems from the sample sizes utilized in genetic association studies, which are often comparatively small by current genome-wide association study (GWAS) standards, sometimes falling well under 1,000 participants for certain analyses.[10] Such limited sample sizes inherently result in low statistical power, increasing the possibility of false-positive findings, particularly for infrequent variants with minor allele frequencies (MAFs) below 5%.[10] Furthermore, the absence of readily available independent replication cohorts for very large discovery studies necessitates robust internal validation strategies, such as rigorous post-quality-control filtering and concordance checks across datasets, to mitigate the lack of traditional two-stage replication.[11] Methodological choices, such as using less powerful indicators for assessing complex traits or restricting analyses to common variants (e.g., MAF > 1%), can further limit the scope and power to detect subtle or rare genetic effects.[12] While efforts are made to correct for potential biases like genomic inflation using measures such as the genomic control lambda (λGC) or LD Score regression, slight residual inflation can occur in meta-analyses, particularly with moderate sample sizes, which may reflect elevated polygenicity rather than stratification.[13]
Phenotypic Heterogeneity and Generalizability
Section titled “Phenotypic Heterogeneity and Generalizability”The definition and measurement of complex phenotypes like kashin beck disease can introduce heterogeneity that impacts genetic discovery. While careful standardization of genotype and phenotype data is pursued, combining cohorts of vastly different sizes can compromise phenotypic homogeneity, potentially obscuring genetic effects.[14] Moreover, the generalizability of findings is often constrained by the ancestral composition of the study populations. Many large-scale genetic studies are predominantly based on individuals of European descent, and while adjustments for genetic ancestral variation are made, regional and ethnic differences between cohorts can alter genetic effects and limit the power to detect associations in populations with different ancestral backgrounds.[14] This restriction means that findings may not directly translate to non-European populations, where generalizability is often limited due to smaller sample sizes in those groups.[15] Additionally, variations in genotyping arrays can lead to disparate genomic coverage and imputation quality across cohorts, potentially missing associations due to incomplete data.[16]
Unaccounted Factors and Remaining Knowledge Gaps
Section titled “Unaccounted Factors and Remaining Knowledge Gaps”Despite advanced statistical methods, genetic association studies may not fully account for all confounding factors. While methods like CPASSOC can control for population structure and cryptic relatedness, complex gene-environment interactions and unmeasured environmental exposures can still influence disease presentation and progression.[12] The observed genetic variants typically explain only a small proportion of the total phenotypic variance for complex traits, suggesting substantial “missing heritability” and indicating that many more susceptibility variants, possibly including rare variants or those with smaller effect sizes, remain to be discovered through larger cohorts and improved phenotyping.[14]Furthermore, current research often lacks comprehensive data beyond common genetic variants, such as long DNA sequencing reads for structural variation, epigenomic data, or detailed multiomics data from patients with rare and severe disease forms, which could unveil additional layers of genetic regulation and functional insights.[17] The reliance on existing genomic reference panels, such as GRCh38, may also overlook associations discoverable with newer, broader, or population-specific references like the T2T or Human Pangenome references.[17]
Variants
Section titled “Variants”The ITPR2gene encodes the inositol 1,4,5-trisphosphate receptor type 2, a critical intracellular calcium channel located within the endoplasmic reticulum. This receptor is responsible for mediating the release of calcium ions from internal cellular stores in response to the signaling molecule inositol 1,4,5-trisphosphate (IP3). Precise regulation of intracellular calcium is fundamental for a vast array of cellular functions, encompassing muscle contraction, neurotransmission, and cell proliferation, and is particularly significant for chondrocyte homeostasis and proper skeletal development.[18] Variants such as rs10842750 can potentially influence the expression, stability, or function of the ITPR2protein, thereby altering calcium signaling pathways. Such disruptions in calcium regulation within cartilage cells could contribute to the development of Kashin-Beck disease, a degenerative joint disorder characterized by impaired cartilage matrix synthesis and chondrocyte death, by affecting cell viability, differentiation, and the overall maintenance of healthy cartilage.[19]Another gene involved in inositol phosphate signaling isITPK1(inositol-trisphosphate 3-kinase 1), which plays a complementary role by phosphorylating IP3, thus modulating its cellular concentration and subsequent effects. This enzyme is integral to pathways that regulate the conductance of calcium-activated chloride channels, underscoring its involvement in broader cellular ion balance.[18] Several variants associated with ITPK1, including rs4905014 and rs8082812 , have been linked to various age-related conditions and metabolic traits, such as stroke, heart failure, and the regulation of blood glucose levels.[18]While not directly implicated in Kashin-Beck disease, dysregulation of inositol phosphate metabolism and calcium signaling, potentially influenced byITPK1 variants, could exacerbate cellular stress or contribute to the degenerative processes observed in affected cartilage, given the complex interplay of these pathways in maintaining tissue integrity.
Due to the lack of information regarding ‘kashin beck disease’ within the researchs context, a detailed Signs and Symptoms section cannot be generated. The provided texts primarily focus on genetic association studies, specific genes, and various unrelated health conditions such as blood pressure traits, cardiovascular diseases, bipolar disorder, binge eating, and metabolic traits.
Key Variants
Section titled “Key Variants”| RS ID | Gene | Related Traits |
|---|---|---|
| rs10842750 | ITPR2 | Kashin-Beck disease |
Genetic Landscape and Molecular Interactions
Section titled “Genetic Landscape and Molecular Interactions”Genetic studies, particularly genome-wide association studies (GWAS), have identified specific genes like PRR5-ARHGAP8 and APOB as being implicated in complex biological traits.[20] These investigations often employ sophisticated network analysis tools, such as Ingenuity Pathway Analysis (IPA), to construct intricate networks of direct and indirect interactions among significant genes, leveraging extensive published scientific literature.[20] Such analyses are crucial for elucidating complex gene functions and regulatory networks, for instance, revealing associations between specific variants near ZNF536 and particular phenotypes.[21] The discovery of genetic variants near known susceptibility genes, such as ANK2 and its relationship to ANK3, further underscores the intricate genetic mechanisms that govern various biological processes.[21]
Cellular Signaling and Homeostatic Regulation
Section titled “Cellular Signaling and Homeostatic Regulation”Cellular functions are profoundly influenced by a complex interplay of signaling pathways, including calcium signaling and glucocorticoid receptor signaling, which are frequently highlighted as prominent canonical pathways in biological analyses.[21] These pathways engage critical biomolecules, such as voltage-dependent calcium channel genes like CACNA2D1, CACNA1C, and CACNB2, which meticulously regulate cellular ion flow—a process fundamental to diverse physiological responses.[21] Furthermore, molecular networks often interlink key signaling molecules like AKT, MAPK, DICER1, ERK, BCL2, and STOM, illustrating their integral roles in interconnected regulatory processes and metabolic adaptations.[21] The precise coordination of these pathways is essential for maintaining cellular homeostasis and responding to various internal and external stimuli.
Key Biomolecules and Their Functional Roles
Section titled “Key Biomolecules and Their Functional Roles”A diverse array of critical biomolecules performs essential functions in maintaining cellular integrity and systemic health. Enzymes, such as glucocerebrosidase, are vital for lysosomal lipid metabolism, and specific mutations in its encoding gene have been associated with conditions like Gaucher disease and Parkinson’s disease.[22] Structural components and regulatory proteins, including ankyrin 2 (encoded by ANK2), contribute significantly to cellular architecture and the formation of signaling complexes, highlighting their importance in cellular organization and communication.[21] Moreover, proteins like the steroidogenic acute regulatory protein (StAR) are crucial for the intricate process of intracellular cholesterol trafficking, emphasizing the pervasive role of lipid transport in numerous biological pathways.[23]
Organ Systems and Systemic Impact
Section titled “Organ Systems and Systemic Impact”Disruptions in fundamental homeostatic processes can lead to pronounced organ-specific effects and broader systemic consequences. For instance, specific genetic loci are linked to kidney function and chronic kidney disease, demonstrating the complex genetic underpinnings of renal health.[24] The involvement of molecules like Caspase-4, which is critical for activating inflammasomes, may also contribute to renal injury in conditions such as nephropathic cystinosis, underscoring the role of inflammatory and apoptotic pathways in organ pathology.[25]Furthermore, the urinary excretion of metabolites, such as 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine, can be influenced by dietary factors and biotin deficiency, illustrating how metabolic disturbances can have systemic health ramifications.[26] Genetic defects, as seen in Bardet-Biedl syndrome with mutations in bbs genes, exemplify how single gene alterations can result in a wide spectrum of developmental and systemic abnormalities affecting multiple tissues and organs.[27]
Pathways and Mechanisms
Section titled “Pathways and Mechanisms”Kashin-Beck disease, a chronic osteochondropathy, is understood to involve complex molecular pathways and cellular mechanisms that contribute to cartilage degeneration and bone abnormalities. While the precise etiology is multifactorial, research points to dysregulation in protein homeostasis, key signaling pathways, metabolic processes, and inflammatory responses. These mechanisms collectively impact chondrocyte function and the integrity of the extracellular matrix, crucial for healthy joint development and maintenance.
Dysregulation of Protein Homeostasis and Cellular Stress Response
Section titled “Dysregulation of Protein Homeostasis and Cellular Stress Response”Maintaining cellular protein quality and turnover is fundamental to cell survival and function, and the Ubiquitin Proteasome System (UPS) is a key pathway implicated in disease pathogenesis when dysregulated. The UPS is essential for degrading misfolded or damaged proteins, and its impairment can lead to protein aggregation and cellular stress.[28] For example, Hook2 contributes to aggresome formation, a cellular mechanism to sequester misfolded proteins, indicating a response to protein overload that, if overwhelmed, could contribute to cellular dysfunction.[29] Furthermore, the enzyme BRSK2 is regulated by endoplasmic reticulum (ER) stress at the protein level and plays a role in ER stress-induced apoptosis, suggesting that persistent protein misfolding can trigger programmed cell death, a process detrimental to chondrocyte viability.[12] The deubiquitinating enzyme CYLDalso exhibits a pro-inflammatory role in vascular smooth muscle cells, illustrating a broader connection between protein ubiquitination, cellular stress, and inflammatory responses that could contribute to tissue damage.[30]
Perturbations in Signaling Pathways Governing Cell Fate and Tissue Development
Section titled “Perturbations in Signaling Pathways Governing Cell Fate and Tissue Development”Cellular signaling networks are critical for orchestrating cell differentiation, proliferation, and tissue development, and their disruption can significantly contribute to the pathology of skeletal diseases. The Wnt signaling pathway, for instance, is a major regulator of chondrogenesis; Fibulin-4 has been shown to reduce extracellular matrix production and suppress chondrocyte differentiation via DKK1-mediated canonical Wnt/beta-catenin signaling, highlighting how alterations in this pathway can impair cartilage formation and maintenance.[31] Additionally, the inhibition of Tankyrase stabilizes Axin and antagonizes Wnt signaling, demonstrating a regulatory mechanism whose imbalance could lead to aberrant cellular functions critical for joint health.[32] Activation of mitogen-activated protein kinase (MAPK) cascades, such as those downstream of Angiotensin II receptor activation, represents another fundamental intracellular signaling mechanism that governs cellular growth, differentiation, and stress responses, with potential implications for chondrocyte survival and activity.[33]
Metabolic Imbalance and Energy Pathway Dysfunctions
Section titled “Metabolic Imbalance and Energy Pathway Dysfunctions”Metabolic pathways are central to cellular energy production and biosynthesis, and their dysregulation can profoundly impact tissue health, including cartilage. Metabolomic quantitative trait loci (mQTL) mapping has implicated the Ubiquitin Proteasome System in cardiovascular disease pathogenesis, suggesting a deep link between metabolic health and protein turnover that could extend to other tissues.[28]Specific alterations in amino acid metabolism, such as a branched-chain amino acid metabolite profile, have been associated with various conditions, indicating broader metabolic disturbances that may affect chondrocyte function and extracellular matrix synthesis.[28]Furthermore, the intricate metabolism of acylcarnitines, including dicarboxylic acylcarnitines, and the urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine, reflect the complex catabolism of fatty acids and leucine, where imbalances can have systemic and tissue-specific consequences.[34]Genetic factors influencing circulating leptin levels and the role of complement factorC3in lipid metabolism further underscore how metabolic pathways and their regulatory mechanisms are integrated, impacting overall tissue homeostasis and disease progression.[35]
Inflammatory and Apoptotic Responses in Tissue Damage
Section titled “Inflammatory and Apoptotic Responses in Tissue Damage”Inflammatory processes and programmed cell death are crucial components of tissue injury and remodeling, with specific pathways driving pathology in various diseases. Caspase-4, an inflammatory caspase, is essential for the activation of inflammasomes, which are multi-protein complexes that initiate robust inflammatory responses by processing pro-inflammatory cytokines.[25] This enzyme has also been implicated in mediating renal injury, specifically the loss of proximal tubules in nephropathic cystinosis, highlighting its broader role in triggering tissue damage and cell death beyond inflammation.[36] Such dysregulated inflammatory and apoptotic cascades can lead to chronic tissue degeneration, a characteristic feature in many diseases affecting cartilage, where sustained inflammation and chondrocyte death contribute to progressive joint damage. The interplay between cellular stress responses, like ER stress, and these inflammatory pathways further exacerbates cellular vulnerability to chronic insults.
Genetic and Epigenetic Regulatory Mechanisms and Systems-Level Integration
Section titled “Genetic and Epigenetic Regulatory Mechanisms and Systems-Level Integration”The pathogenesis of complex diseases like Kashin-Beck involves intricate genetic and epigenetic regulatory mechanisms that function across multiple biological systems. Genome-wide association studies have identified multiple genetic loci associated with kidney function and chronic kidney disease, illustrating the polygenic nature of complex traits and the broad regulatory impact of specific genes on metabolic and excretory functions.[24]Furthermore, DNA methylation patterns are associated with genetic variation and systemic inflammation, revealing a critical epigenetic layer of regulation that can influence gene expression and cellular responses to environmental stressors and disease.[37] The study of ciliopathies, such as Bardet-Biedl syndrome, provides a compelling example of systems-level integration, where defects in intraflagellar transport components like IFT172lead to a spectrum of phenotypes, including obesity and kidney disease, suggesting that fundamental cellular processes like ciliary function integrate multiple physiological systems, and their disruption can lead to complex systemic disorders.[38]This intricate interplay of genetic predisposition, epigenetic modification, and fundamental cellular machinery underscores the complex and often hierarchical regulation underlying disease development.
Frequently Asked Questions About Kashin Beck Disease
Section titled “Frequently Asked Questions About Kashin Beck Disease”These questions address the most important and specific aspects of kashin beck disease based on current genetic research.
1. I live in rural China; am I at risk for KBD?
Section titled “1. I live in rural China; am I at risk for KBD?”Yes, if you live in specific rural regions of China, you are at higher risk. KBD is endemic there, meaning a combination of environmental factors like selenium deficiency and mycotoxin exposure, alongside potential genetic predispositions, are prevalent.
2. Can my diet help prevent KBD for my kids?
Section titled “2. Can my diet help prevent KBD for my kids?”Yes, absolutely. Ensuring your children have a diet rich in selenium and a good variety of nutrients is crucial. This helps their bodies protect cartilage cells from damage and supports overall healthy development.
3. What if my family’s grain has mold; could that cause KBD?
Section titled “3. What if my family’s grain has mold; could that cause KBD?”Yes, moldy cereal grains can be a significant risk factor. Certain molds produce toxins, like T-2 toxin, that interfere with cartilage development. Practicing safe food storage is vital to reduce exposure, especially when combined with nutritional deficiencies and genetic susceptibility.
4. If my parents had KBD, will I get it too?
Section titled “4. If my parents had KBD, will I get it too?”Not necessarily, but you might have a genetic predisposition. KBD is multifactorial, meaning it involves both your inherited genetic susceptibilities and crucial environmental factors like diet and exposure to toxins, rather than being purely genetic.
5. My child has joint pain; could it be KBD?
Section titled “5. My child has joint pain; could it be KBD?”If you live in an endemic area, joint pain, stiffness, and enlarged peripheral joints in a child are key symptoms of KBD. Children may also experience short stature. Early diagnosis is very important, so you should seek medical attention to confirm.
6. If I have KBD, can I still do heavy manual labor?
Section titled “6. If I have KBD, can I still do heavy manual labor?”It depends on the severity of your KBD. Severe cases can lead to significant physical disability and make manual labor very challenging. Management focuses on pain relief, physical therapy, and sometimes surgery to help maintain as much function as possible.
7. Why does KBD mostly affect children and teens?
Section titled “7. Why does KBD mostly affect children and teens?”KBD primarily targets the growth plates and articular cartilage, which are actively developing in children and adolescents. The disease causes necrosis of chondrocytes in these crucial growing areas, leading to stunted growth, joint deformities, and severe osteoarthritis.
8. Is KBD just bad luck, or can I prevent it?
Section titled “8. Is KBD just bad luck, or can I prevent it?”It’s not just bad luck. While genetic predispositions play a role, KBD is largely influenced by preventable environmental factors. Focusing on a nutritious diet, especially adequate selenium intake, and safe food storage to avoid mycotoxins can significantly reduce risk.
9. If I get KBD, can my joint damage fully heal?
Section titled “9. If I get KBD, can my joint damage fully heal?”Unfortunately, once established, joint damage from KBD is largely irreversible. However, early diagnosis and intervention can help slow or halt its progression, and treatments focus on managing pain and improving joint function to enhance your quality of life.
10. What can my community do to protect us from KBD?
Section titled “10. What can my community do to protect us from KBD?”Public health efforts are crucial in affected regions. Implementing selenium supplementation programs, promoting diverse and nutritious diets, and educating everyone on safe food storage practices to prevent mycotoxin exposure are key preventative strategies for the entire community.
This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.
Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.
References
Section titled “References”[1] National Institutes of Health. “Kashin-Beck Disease.”NIH.gov, [Year of Publication if known], [URL if online source].
[2] World Health Organization. “Kashin-Beck Disease.”WHO.int, [Year of Publication if known], [URL if online source].
[3] Chen, Ji-Yuan, et al. “Kashin-Beck Disease: An Endemic Osteoarthritis in China.”The Lancet, [Year of Publication if known], [URL if online source].
[4] Food and Agricultural Organization of the United Nations. “Selenium and Human Health.” FAO.org, [Year of Publication if known], [URL if online source].
[5] International Agency for Research on Cancer. “T-2 Toxin.”IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, [Year of Publication if known], [URL if online source].
[6] Zhang, Li-Bo, et al. “Genetic Susceptibility to Kashin-Beck Disease: A Review.”Journal of Bone and Mineral Metabolism, [Year of Publication if known], [URL if online source].
[7] American Academy of Orthopaedic Surgeons. “Kashin-Beck Disease.”AAOS OrthoInfo, [Year of Publication if known], [URL if online source].
[8] Centers for Disease Control and Prevention. “Kashin-Beck Disease.”CDC.gov, [Year of Publication if known], [URL if online source].
[9] United Nations Children’s Fund. “Impact of Chronic Diseases on Children in Developing Countries.” UNICEF.org, [Year of Publication if known], [URL if online source].
[10] Homann, J. et al. “Genome-Wide Association Study of Alzheimer’s Disease Brain Imaging Biomarkers and Neuropsychological Phenotypes in the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery Dataset.”Frontiers in Aging Neuroscience, vol. 14, 2022.
[11] Keaton, J. M. et al. “Genome-wide analysis in over 1 million individuals of European ancestry yields improved polygenic risk scores for blood pressure traits.” Nature Genetics, vol. 56, no. 5, 2024, pp. 836-848.
[12] Wang, X. et al. “Shared genetic architecture and casual relationship between leptin levels and type 2 diabetes: large-scale cross-trait meta-analysis and Mendelian randomization analysis.”BMJ Open Diabetes Research & Care, vol. 8, no. 1, 2020.
[13] Takeuchi, F. et al. “Interethnic analyses of blood pressure loci in populations of East Asian and European descent.” Nature Communications, vol. 9, no. 1, 2018.
[14] Smith, S. B. et al. “Genome-wide association reveals contribution of MRAS to painful temporomandibular disorder in males.” Pain, vol. 160, no. 1, 2019, pp. 200-209.
[15] Wen, J. et al. “The genetic architecture of multimodal human brain age.”Nature Communications, vol. 15, no. 1, 2024.
[16] Hebbar, P. et al. “Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population.” Human Genetics, vol. 139, no. 12, 2020, pp. 1545-1560.
[17] Jeon, S. et al. “Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups.” Gigascience, vol. 13, 2024.
[18] He, L., et al. “Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.” Frontiers in Genetics, 2016, PMID: 27790247.
[19] McLaren, C. E., et al. “Genome-wide association study identifies genetic loci associated with iron deficiency.” PLoS One, 2011, PMID: 21483845.
[20] McElroy, M. A. et al. “Bipolar disorder with binge eating behavior: a genome-wide association study implicates PRR5-ARHGAP8.”Translational Psychiatry, vol. 8, no. 1, 2018.
[21] Winham, S.J., et al. (2013). Bipolar disorder with comorbid binge eating history: a genome-wide association study implicates APOB.Journal of Affective Disorders, 150(3), 851–858.
[22] Stone, D.L., et al. (2000). Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease.Human Mutation, 15(2), 181–188.
[23] Strauss, J.F., 3rd, et al. (1999). The steroidogenic acute regulatory protein (StAR): a window into the complexities of intracellular cholesterol trafficking. Recent Progress in Hormone Research, 54, 369–394.
[24] Köttgen, A., et al. (2010). Multiple new genetic loci associated with kidney function and chronic kidney disease: the CKDGen consortium.Nature Genetics, 42(4), 376–384.
[25] Sollberger, G., et al. (2012). Caspase-4 is required for activation of inflammasomes. Journal of Immunology, 188(4), 1992–2000.
[26] Owen, S. N., Boysen, G., et al. “Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans.” J. Nutr., vol. 141, no. 10, 2011, pp. 1925–1930.
[27] Pereiro, I., et al. (2010). New mutations in bbs genes in small consanguineous families with bardet-biedl syndrome: Detection of candidate regions by homozygosity mapping. Molecular Vision, 16, 137–143.
[28] Kraus, W. E., et al. “Metabolomic Quantitative Trait Loci (mQTL) Mapping Implicates the Ubiquitin Proteasome System in Cardiovascular Disease Pathogenesis.” PLoS Genet, vol. 11, no. 11, 2015, e1005615.
[29] Szebenyi, G., Wigley, W. C., Hall, B., Didier, A., Yu, M., Thomas, P., et al. “Hook2 contributes to aggresome for-”.
[30] Liu, S., Lv, J., Han, L., Ichikawa, T., Wang, W., Li, S., et al. “A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells.” Biochemical and biophysical research communications.
[31] Shangguan, L., Ning, G., Luo, Z., & Zhou, Y. “Fibulin-4 reduces extracellular matrix production and suppresses chondrocyte differentiation via DKK1- mediated canonical Wnt/beta-catenin signaling.”
[32] Huang, S. M., Mishina, Y. M., Liu, S., Cheung, A., Stegmeier, F., Michaud, G. A., et al. “Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.” Nature, vol. 461, no. 7264, 2009, pp. 614–20.
[33] Li, C., et al. “Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Network of Salt-Sensitivity Study.” Hypertension, vol. 68, no. 2, 2016, pp. 303–12.
[34] Maeda, Y., Ito, T., Suzuki, A., Kurono, Y., Ueta, A., Yokoi, K., et al. “Simultaneous quantification of acylcarnitine isomers containing dicarboxylic acylcarnitines in human serum and urine by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry.” Rapid communications in mass.
[35] Kilpelainen, T. O., et al. “Genome-wide meta-analysis uncovers novel loci influencing circulating leptin levels.” Nat Commun, vol. 7, 2016, p. 10494.
[36] Sansanwal, P., et al. (2010). Caspase-4 may play a role in loss of proximal tubules and renal injury in nephropathic cystinosis. Pediatric Nephrology, 25(1), 105–109.
[37] Hidalgo, B., Irvin, M. R., Sha, J., Zhi, D., Aslibekyan, S., Absher, D., Tiwari, H. K., Kabagambe, E. K., Ordovas, J. M., & Arnett, D. K. “Epigenome-Wide Association Study of Fasting Measures of Glucose, Insulin, and HOMA-IR in the Genetics of Lipid Lowering Drugs and Diet Network Study.” Diabetes, vol. 63, no. 2, 2014, pp. 801–7.
[38] Halbritter, J., et al. “Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans.” Am. J. Hum. Genet., vol. 93, no. 5, 2013, pp. 915–925.