Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.
Maintaining the integrity of brain barriers is critical for a healthy central nervous system. While extensive research has focused on the blood-brain barrier (BBB) of the brain vasculature and blood-cerebrospinal fluid barrier (BCSFB) of the choroid plexus, the barriers formed by the meninges have not received as much attention. These membranes create a barrier between the brain and cerebrospinal fluid (CSF), as well as between CSF and blood. Recent studies have revealed that this barrier has been implicated in the development of neurological and immunological disorders. In order to gain a deeper comprehension of the functioning and significance of the meningeal barriers, sophisticated models of these barriers, need to be created. The aim of this paper is to investigate the characteristics of commercially available primary leptomeningeal cells (LMCs) that form the meningeal barriers, in a cultured environment, including their morphology, proteomics, and barrier properties, and to determine whether passaging of these cells affects their behaviour in comparison to their in vivo state. The results indicate that higher passage numbers significantly alter the morphology and protein localisation and expression of the LMCs. Furthermore, the primary cell culture co-stained for S100A6 and E-cadherin suggesting it is a co-culture of both pial and arachnoid cells. Additionally, cultured LMCs showed an increase in vimentin and cytokeratin expression and a lack of junctional proteins localisation on the cell membrane, which could suggest loss of epithelial properties due to culture, preventing barrier formation. This study shows that the LMCs may be a co-culture of pial and arachnoid cells, that the optimal LMC passage range is between passages two and five for experimentation and that the primary human LMCs form a weak barrier when in culture.Graphical abstract
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in TMEM161B , which encodes a multi-pass transmembrane protein of unknown function. Tmem161b null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. Tmem161b depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the Tmem161b null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify TMEM161B as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.
For over three decades, the Permanent Committee of the International Congresses of Human Genetics has served the purpose of selecting a host and site for the quadrennial Congress, which is due next in 2001. The Committee has statutes and consists of one voting representative from 38 nations and other ex officio members, much like the General Assembly of the United Nations. It meets twice during each International Congress, otherwise conducting its business by mail and telecommunication. Its structure could be the beginnings of a truly global democratic body of human geneticists to address other issues and to serve other purposes, as human genetics becomes increasingly international, as inevitably it must.
