Clinical and cellular features in patients with primary autosomal recessive microcephaly and a novel CDK5RAP2 mutation

Background Primary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist. Methods/Results We sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent. Conclusion These results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3

An international intercomparison of stable carbon isotope composition measurements of dissolved inorganic carbon in seawater

We report results of an intercomparison of stable carbon isotope ratio measurements in seawater dissolved inorganic carbon (δ 13C‐DIC) which involved 16 participating laboratories from various parts of the world. The intercomparison involved distribution of samples of a Certified Reference Material for seawater DIC concentration and alkalinity and a preserved sample of deep seawater collected at 4000 m in the northeastern Atlantic Ocean. The between‐lab standard deviation of reported uncorrected values measured with diverse analytical, detection, and calibration methods was 0.11‰ (1σ ). The multi‐lab average δ 13C‐DIC value reported for the deep seawater sample was consistent within 0.1‰ with historical measured values for the same water mass. Application of a correction procedure based on a consensus value for the distributed reference material, improved the between‐lab standard deviation to 0.06‰. The magnitude of the corrections were similar to those used to correct independent data sets using crossover comparisons, where deep water analyses from different cruises are compared at nearby locations. Our results demonstrate that the accuracy/uncertainty target proposed by the Global Ocean Observing System (±0.05‰) is attainable, but only if an aqueous phase reference material for δ 13C‐DIC is made available and used by the measurement community. Our results imply that existing Certified Reference Materials used for seawater DIC and alkalinity quality control are suitable for this purpose, if a “Certified” or internally consistent “consensus” value for δ 13C‐DIC can be assigned to various batches.publishedVersio

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

OBJECTIVE: To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). METHODS: We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. RESULTS: In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. INTERPRETATION: We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease

Selberg Supertrace Formula for Super Riemann Surfaces III: Bordered Super Riemann Surfaces

This paper is the third in a sequel to develop a super-analogue of the classical Selberg trace formula, the Selberg supertrace formula. It deals with bordered super Riemann surfaces. The theory of bordered super Riemann surfaces is outlined, and the corresponding Selberg supertrace formula is developed. The analytic properties of the Selberg super zeta-functions on bordered super Riemann surfaces are discussed, and super-determinants of Dirac-Laplace operators on bordered super Riemann surfaces are calculated in terms of Selberg super zeta-functions.Comment: 43 pages, amste

Combined immunodeficiency develops with age in immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2)

The autosomal recessive immunodeficiency-centromeric instability-facial anomalies syndrome (ICF) is characterized by immunodeficiency, developmental delay, and facial anomalies. ICF2, caused by biallelic ZBTB24 gene mutations, is acknowledged primarily as an isolated B-cell defect. Here, we extend the phenotype spectrum by describing, in particular, for the first time the development of a combined immune defect throughout the disease course as well as putative autoimmune phenomena such as granulomatous hepatitis and nephritis. We also demonstrate impaired cell-proliferation and increased cell death of immune and non-immune cells as well as data suggesting a chromosome separation defect in addition to the known chromosome condensation defect