Sterol profiles in plasma and erythrocyte membranes in patients with Smith-Lemli-Opitz syndrome: a six-year experience

Background: This study reports our experience over the last six years in the diagnosis of Smith-Lemli-Opitz syndrome and other inborn errors of cholesterol biosynthesis. Methods: Gas chromatography/mass spectrometry was used to obtain sterol profiles in plasma and erythrocyte membranes of suspected patients. Results: Plasma sterol reference values calculated in unaffected subjects (ns276) were in agreement with those previously reported. Among patients investigated from 2005 to 2010, we report 16 patients affected by Smith-Lemli-Opitz syndrome, three of whom represent new cases and 13 of whom were follow-up patients. In this period we also identified a new case of chondrodysplasia punctata 2 X-linked. The estimated incidence obtained for Smith-Lemli-Opitz syndrome was 1:93 suspected patients (1.08%). We also studied the effect of storage on the dehydrocholesterols/ cholesterol ratio in plasma and erythrocyte membranes of patients affected by Smith-Lemli-Opitz syndrome stored at –208C for up to 22 and 20 months, respectively. A significant negative linear correlation between storage time and the dehydrocholesterols/cholesterol ratio was identified in both plasma and erythrocyte membranes. The decrease in the dehydrocholesterols/cholesterol ratio in erythrocyte membranes was at least two-fold higher than in plasma. Conclusions: The results of this study may be helpful for diagnosis and interpretation of data in patients with findings suggestive of a cholesterol biosynthesis defect

Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth

Burkitt lymphoma in a child with osteogenesis imperfecta

No Abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48778/1/20439_ftp.pd

Vitalism in Early Modern Medical and Philosophical Thought

Vitalism is a notoriously deceptive term. It is very often defined as the view, in biology, in early modern medicine and differently, in early modern philosophy, that living beings differ from the rest of the physical universe due to their possessing an additional ‘life-force’, ‘vital principle’, ‘entelechy’, enormon or élan vital. Such definitions most often have an explicit pejorative dimension: vitalism is a primitive or archaic view, that has somehow survived the emergence of modern science (the latter being defined in many different ways, from demystified Cartesian reductionism to experimental medicine, biochemistry or genetics: Cimino and Duchesneau eds. 1997, Normandin and Wolfe eds. 2013). Such dismissive definitions of vitalism are meant to dispense with argument or analysis. Curiously, the term has gained some popularity in English-language scholarship on early modern philosophy in the past few decades, where it is used without any pejorative dimension, to refer to a kind of ‘active matter’ view, in which matter is not reducible to the (mechanistic) properties of size, shape and motion, possessing instead some internal dynamism or activity (see e.g. James 1999, Boyle 2018, Borcherding forthcoming). The latter meaning is close to what the Cambridge Platonist Ralph Cudworth termed ‘hylozoism’, namely the attribution of life, agency or mind to matter, and he implicitly targeted several figures I shall mention here, notably Margaret Cavendish and Francis Glisson, for holding this view. However, one point I shall make in this entry is that when vitalism first appears by name, and as a self-designation, in the Montpellier School (associated with the Faculty of Medicine at the University of Montpellier, in the second half of the eighteenth century; thus vitalisme appears first, followed shortly thereafter by Vitalismus in German, with ‘vitalism’ appearing in English publications only in the early nineteenth century: Toepfer 2011), it is quite different from both the more ‘supernatural’ view described above – chiefly espoused by its rather obsessive opponents – and from the more neutral, but also de-biologized philosophical view (that of e.g. Cavendish or Conway who are, broadly speaking naturalists). Rather than appealing to a metaphysics of vital force, or of self-organizing matter, this version of vitalism, which I shall refer to as ‘medical vitalism’, seems to be more of a ‘systemic’ theory: an attempt to grasp and describe top-level (‘organizational’, ‘organismic’, ‘holistic’) features of living systems (Wolfe 2017, 2019). In this entry I seek to introduce some periodization in our thinking about early modern (and Enlightenment) vitalism, emphasizing the difference between the seventeenth-century context and that of the following generations – culminating in the ideas of the Montpellier School. This periodization should also function as a kind of taxonomy or at least distinction between some basic types of vitalism. As I discuss in closing, these distinctions can cut across the texts and figures we are dealing with, differently: metaphysical vs. non-metaphysical vitalism, philosophical vs. medical vitalism, medical vs. ‘embryological’ vitalism, and so on. A difference I can only mention but not explore in detail is that the more medically grounded, ‘organismic’ vitalism is significantly post-Cartesian while the more biological/embryological vitalism is, inasmuch as it is a dynamic, self-organizing matter theory, an extension of Renaissance ideas (chymiatry, Galenism and in general theories of medical spirits). I examine successively vitalism’s Renaissance prehistory, its proliferation as ‘vital matter theory’ in seventeenth-century England (in authors such as Cavendish, Conway and Glisson, with brief considerations on Harvey and van Helmont), and its mature expression in eighteenth-century Montpellier (notably with Bordeu and Ménuret de Chambaud)

Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 12

In this contribution, new data concerning bryophytes, fungi and lichens of the Italian flora are presented. It includes new records, confirmations or exclusions for the bryophyte genera Acaulon, Campylopus, En-tosthodon, Homomallium, Pseudohygrohypnum, and Thuidium, the fungal genera Entoloma, Cortinarius, Mycenella, Oxyporus, and Psathyrella and the lichen genera Anaptychia, Athallia, Baeomyces, Bagliettoa, Calicium, Nephroma, Pectenia, Phaeophyscia, Polyblastia, Protoparmeliopsis, Pyrenula, Ramalina, and San-guineodiscus

Mutations in 3 genes (MKS3, CC2D2A and RPGRIP1L) cause COACH syndrome (Joubert syndrome with congenital hepatic fibrosis)

OBJECTIVE: To identify genetic causes of COACH syndrome BACKGROUND: COACH syndrome is a rare autosomal recessive disorder characterised by Cerebellar vermis hypoplasia, Oligophrenia (developmental delay/mental retardation), Ataxia, Coloboma, and Hepatic fibrosis. The vermis hypoplasia falls in a spectrum of mid-hindbrain malformation called the molar tooth sign (MTS), making COACH a Joubert syndrome related disorder (JSRD). METHODS: In a cohort of 251 families with JSRD, 26 subjects in 23 families met criteria for COACH syndrome, defined as JSRD plus clinically apparent liver disease. Diagnostic criteria for JSRD were clinical findings (intellectual impairment, hypotonia, ataxia) plus supportive brain imaging findings (MTS or cerebellar vermis hypoplasia). MKS3/TMEM67 was sequenced in all subjects for whom DNA was available. In COACH subjects without MKS3 mutations, CC2D2A, RPGRIP1L and CEP290 were also sequenced. RESUlTS: 19/23 families (83%) with COACH syndrome carried MKS3 mutations, compared to 2/209 (1%) with JSRD but no liver disease. Two other families with COACH carried CC2D2A mutations, one family carried RPGRIP1L mutations, and one lacked mutations in MKS3, CC2D2A, RPGRIP1L and CEP290. Liver biopsies from three subjects, each with mutations in one of the three genes, revealed changes within the congenital hepatic fibrosis/ductal plate malformation spectrum. In JSRD with and without liver disease, MKS3 mutations account for 21/232 families (9%). CONCLUSIONS: Mutations in MKS3 are responsible for the majority of COACH syndrome, with minor contributions from CC2D2A and RPGRIP1L; therefore, MKS3 should be the first gene tested in patients with JSRD plus liver disease and/or coloboma, followed by CC2D2A and RPGRIP1L

Notulae to the Italian flora of algae, bryophytes, fungi and lichens: 13

In this contribution, new data concerning bryophytes, fungi and lichens of the Italian flora are presented. It includes new records and confirmations for the bryophyte genera Bryum, Cryphaea, Didymodon, and Grimmia; the fungal genera Bryostigma, Cercidospora, Conocybe, Cortinarius, Endococcus, Inocybe, Psathyrella, and Sphaerellothecium; the lichen genera Agonimia, Anisomeridium, Bilimbia, Diplotomma, Gyalecta, Huneckia, Lecidella, Lempholemma, Myriolecis, Nephroma, Pannaria, Pycnothelia, Pyrrhospora, Rinodina, Stereocaulon, Thalloidima, Trapelia, Usnea, Variospora, and Verrucaria

DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes.

Weaver syndrome (WS), an overgrowth/intellectual disability syndrome (OGID), is caused by pathogenic variants in the histone methyltransferase EZH2, which encodes a core component of the Polycomb repressive complex-2 (PRC2). Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism. We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID. The discovery of a functionally relevant signature with utility for diagnostic classification of sequence variants in EZH2, EED, and SUZ12 supports the emerging paradigm shift for implementation of DNAm signatures into diagnostics and translational research

Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome wide siRNA screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies

Mutations in STAMBP, encoding a deubiquitinating enzyme, cause microcephaly-capillary malformation syndrome

Microcephaly–capillary malformation (MIC-CAP) syndrome is characterized by severe microcephaly with progressive cortical atrophy, intractable epilepsy, profound developmental delay and multiple small capillary malformations on the skin. We used whole-exome sequencing of five patients with MIC-CAP syndrome and identified recessive mutations in STAMBP, a gene encoding the deubiquitinating (DUB) isopeptidase STAMBP (STAM-binding protein, also known as AMSH, associated molecule with the SH3 domain of STAM) that has a key role in cell surface receptor–mediated endocytosis and sorting. Patient cell lines showed reduced STAMBP expression associated with accumulation of ubiquitin-conjugated protein aggregates, elevated apoptosis and insensitive activation of the RAS-MAPK and PI3K-AKT-mTOR pathways. The latter cellular phenotype is notable considering the established connection between these pathways and their association with vascular and capillary malformations. Furthermore, our findings of a congenital human disorder caused by a defective DUB protein that functions in endocytosis implicates ubiquitin-conjugate aggregation and elevated apoptosis as factors potentially influencing the progressive neuronal loss underlying MIC-CAP syndrome