Search

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients. [ABSTRACT FROM AUTHOR]

Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants in calcyphosine-like gene (CAPSL) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of Capsl resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/migration, recapitulating the human FEVR phenotypes. CAPSL-depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment, and filopodia/lamellipodia formation, as well as disrupted collective cell migration. Transcriptomic and proteomic profiling revealed that CAPSL abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of CAPSL-depleted HRECs and c-MYC-depleted human umbilical vein endothelial cells uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL, which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR.

Familial exudative vitreoretinopathy (FEVR) is a severe genetic disorder characterized by incomplete vascularization of the peripheral retina and associated symptoms that can lead to vision loss. However, the underlying genetic causes of approximately 50% of FEVR cases remain unknown. Here, we report two heterozygous variants in calcyphosine-like gene ( CAPSL ) that is associated with FEVR. Both variants exhibited compromised CAPSL protein expression. Vascular endothelial cell (EC)-specific inactivation of Capsl resulted in delayed radial/vertical vascular progression, compromised endothelial proliferation/migration, recapitulating the human FEVR phenotypes. CAPSL -depleted human retinal microvascular endothelial cells (HRECs) exhibited impaired tube formation, decreased cell proliferation, disrupted cell polarity establishment, and filopodia/lamellipodia formation, as well as disrupted collective cell migration. Transcriptomic and proteomic profiling revealed that CAPSL abolition inhibited the MYC signaling axis, in which the expression of core MYC targeted genes were profoundly decreased. Furthermore, a combined analysis of CAPSL -depleted HRECs and c-MYC -depleted human umbilical vein endothelial cells uncovered similar transcription patterns. Collectively, this study reports a novel FEVR-associated candidate gene, CAPSL , which provides valuable information for genetic counseling of FEVR. This study also reveals that compromised CAPSL function may cause FEVR through MYC axis, shedding light on the potential involvement of MYC signaling in the pathogenesis of FEVR., Competing Interests: WL, SL, MY, JM, LL, PF, QX, LH, PZ, ZY, XZ No competing interests declared, (© 2024, Liu, Li, Yang et al.)

In the past few years, several genes outside the MHC region have been described as new susceptibility genetic factors to type 1 diabetes. An association between CAPSL-rs1445898 and type 1 diabetes was reported in a large white population and corroborated in a genome-wide analysis, which also found an association with IL7R, which is located adjacent to CAPSL. The aim of this study was to replicate the aforementioned associations in independent cohorts. We analysed two CAPSL (rs1010601 and rs1445898) and three IL7R (rs6897932, rs987106 and rs3194051) polymorphisms. All these single nucleotide polymorphisms (SNPs) were genotyped using TaqMan minor groove binder chemistry in 301 unrelated Spanish type 1 diabetes patients and 646 healthy controls. Additionally, the associated CAPSL SNP rs1445898 was genotyped in a Dutch cohort consisting of 429 type 1 diabetes patients and 720 healthy controls. The homozygous mutant genotype of the CAPSL SNP rs1445898 showed a trend towards a protective effect in the overall Spanish cohort (OR [95% CI] 0.70 [0.44–1.09]; p = 0.09) and in the Dutch cohort (OR [95% CI] 0.74 [0.51–1.05]; p = 0.09). Pooling of both cohorts was performed, yielding a statistically significant difference (Mantel–Haenszel OR 0.71; p = 0.005). This protective effect was significantly different in early-onset vs late-onset Spanish patients (OR [95% CI] 0.26 [0.10–0.65]; p = 0.001). Similarly, in the early-onset subgroup, the homozygous mutant genotype of the IL7R SNP rs6897932 showed a similar protective effect (OR [95% CI] 0.18 [0.02–0.94]; p = 0.02). In summary, we describe an independent replication of the association between the CAPSL-IL7R locus and type 1 diabetes, especially for early-onset type 1 diabetes patients. [ABSTRACT FROM AUTHOR]

The CAPSL Integrated Protocol Environment effort aims at providing an intuitive and expressive language for specifying cryptographic authentication and key distribution protocols and supporting interfaces to various analysis tools. The CAPSL Intermediate Language (CIL) has been designed with the emphasis on simplifying translators from CIL to other analysis tools. In this paper we describe the design of a CIL-to-Spin connector. We describe how CIL concepts are translated into Spin and propose a general method to model the behaviors of honest principals and the intruder. Based on the method, a prototype connector has been implemented in Gentle, which automatically translates CIL specifications to Promela codes and LTL formulae, thus greatly simplifying the modeling and analysis process. [ABSTRACT FROM AUTHOR]

Secure communication generally begins with a~connection establishment phase in which messages are exchanged by client and server protocol software to generate, share, and use secret data or keys. This message exchange is referred to as an authentication or key distribution cryptographic protocol. CAPSL is a formal language for specifying cryptographic protocols. It is also useful for addressing the correctness of the protocols on an abstract level, rather than the strength of the underlying cryptographic algorithms. We outline the design principles of CAPSL and its integrated specification and analysis environment. Protocols for secure group management are essential in applications that are concerned with confidential authenticated communication among coalition members, authenticated group decisions, or the secure administration of group membership and access control. We will also discuss our progress on designing a new extension of CAPSL for multicast protocols, called MuCAPSL.