Further supporting evidence for REEP1 phenotypic and allelic heterogeneity.

Heterozygous mutations in REEP1 (MIM #609139) encoding the receptor expression-enhancing protein 1 (REEP1) are a well-recognized and relatively frequent cause of autosomal dominant hereditary spastic paraplegia (HSP), SPG31.1 REEP1 localizes in the mitochondria and endoplasmic reticulum (ER) and facilitates ER-mitochondria interactions.2 In addition to the HSP phenotype, REEP1 has been associated with an autosomal dominant spinal type of Charcot-Marie-Tooth disease in 2 families.3 More recently, a patient with homozygous REEP1 mutation with a much more severe phenotype akin to spinal muscular atrophy with respiratory distress type 1 (SMARD1) was reported.4 In this report, we present a patient with a homozygous mutation in REEP1 manifesting a severe congenital distal spinal muscular atrophy (SMA) with diaphragmatic paralysis, expanding the phenotype from mild autosomal dominant HSP through to severe recessive distal SMA pattern

Structure and specificity of T cell receptor gamma/delta on major histocompatibility complex antigen-specific CD3+, CD4-, CD8- T lymphocytes.

Analyses of TCR-bearing murine and human T cells have defined a unique subpopulation of T cells that express the TCR-gamma/delta proteins. The specificity of TCR-gamma/delta T cells and their role in the immune response have not yet been elucidated. Here we examine alloreactive TCR-gamma/delta T cell lines and clones that recognize MHC-encoded antigens. A BALB/c nu/nu (H-2d)-derived H-2k specific T cell line and derived clones were both cytolytic and released lymphokines after recognition of a non-classical H-2 antigen encoded in the TL region of the MHC. These cells expressed the V gamma 2/C gamma 1 protein in association with a TCR-delta gene product encoded by a Va gene segment rearranged to two D delta and one J delta variable elements. A second MHC-specific B10 nu/nu (H-2b) TCR-gamma/delta T cell line appeared to recognize a classical H-2D-encoded MHC molecule and expressed a distinct V gamma/C gamma 4-encoded protein. These data suggest that many TCR-gamma/delta-expressing T cells may recognize MHC-linked antigens encoded within distinct subregions of the MHC. The role of MHC-specific TCR-gamma/delta cells in immune responses and their immunological significance are discussed

PRUNE1: a disease-causing gene for secondary microcephaly

In their Letter to the Editor, Karakaya et al. (2017) present an interesting case report describing the clinical course involving secondary microcephaly of a 3-year-old Turkish boy found to be homozygous for a frameshift mutation in PRUNE1 identified through whole exome sequencing. The child presented with congenital hypotonia, contractures and global developmental delay with respiratory insufficiency and seizures developing in the first year of life. The authors note that the affected child’s head circumference plotted on the 75th centile at birth, and that by 38 months of age he had developed microcephaly. Neuroimaging at 14 months revealed cerebral and cerebellar atrophy consistent with other patients described with Prune syndrome (Karaca et al., 2015; Costain et al., 2017; Zollo et al., 2017). Although the child had abnormal neurology from birth, there was a period of early developmental regression. Peripheral spasticity in the lower extremities and optic atrophy were not documented until 38 months. In addition to the PRUNE1 variant, Karakaya et al. also identified a second homozygous variant in the CCDC14 gene in the Turkish child’s whole exome sequencing data that, while listed to have an allele count of 108 in the current Genome Aggregation Database (gnomAD) release, is notably absent in homozygous fashion (Lek et al., 2016). CCDC14 is known to be expressed in human brain, reported to negatively regulate centriole duplication and interact with proteins previously associated with primary microcephaly (Firat-Karalar et al., 2014). Thus, while it seems likely that the homozygous PRUNE1 variant is primarily responsible for the clinical presentation in the Turkish child, it is impossible to determine whether there may be any phenotypical contribution from this additional homozygous sequence variant. Recently, Costain et al. (2017) described a homozygous consensus splice site variant in PRUNE1 (c.521-2A4G; NM_021222.1) in a 2-year-old Oji-Cre male who presented with congenital hypotonia and talipes, whose head circumference was large at birth ( +3 standard deviations), but by 2 years and 2 months plotted on the 50th centile, with a weight and height on the 95th and 75th centiles, respectively. However, it should be noted that the child’s father is macrocephalic ( +4 standard deviations), the published clinical photographs at 2 years 5 months of age illustrate bitemporal narrowing, a sloping forehead and large ears, consistent with a developing microcephaly, and neuroimaging revealed cortical and cerebellar atrophy. He developed respiratory insufficiency shortly after birth, and infantile spasms in the first year of life (Costain et al., 2017). It remains to be determined how the phenotypical outcomes stemming from proposed loss-of-function mutations defined by Karakaya et al. and Costain et al., relate to missense mutations published by Karaca et al. and also Zollo et al., which are likely to involve at least partial gain-of-function outcomes in PRUNE1 activity. However, as more cases are investigated and published, the phenotype associated with autosomal recessive Prune neurodevelopmental disorder, and the functional outcomes of PRUNE1 mutation, are becoming clearer. It is now apparent that while some patients have a small head at birth and others a head circumference in the normal range, the key component of the microcephaly is that it is progressive, and associated with characteristic neuroimaging findings with a thin or hypoplastic corpus callosum and cortical and cerebellar atrophy developing in early childhood. Although all patients with Prune syndrome described to date are neurologically impaired from birth, there also appears to be a neurodegenerative component with progression of the disorder. In our manuscript, we described clinical overlap of Prune syndrome with the neurodegenerative condition associated with homozygous mutations in TBCD (Zollo et al., 2017). TBCD encodes one of the five tubulin-specific chaperones that are required for a/b-tubulin de novo heterodimer formation and the disorder is characterized by developmental regression, seizures, optic atrophy and secondary microcephaly, cortical atrophy with delayed myelination, cerebellar atrophy and thinned corpus callosum (Edvardson et al., 2016; Flex et al., 2016; Miyake et al., 2016; Pode-Shakked et al., 2017). The neurodegenerative phenotype documented in the Turkish child by Karakaya et al. further demonstrates the similarities with the TBCD disorder and Prune syndrome, and confirms optic atrophy to be a feature of Prune syndrome. Interestingly, it is also becoming clear that respiratory insufficiency is a common feature of Prune syndrome, having been documented by Karakaya et al. and in the Oji-Cre child, as well as the youngest affected Omani child described in our manuscript

The effects of an intronic polymorphism in TOMM40 and APOE genotypes in sporadic inclusion body myositis.

A previous study showed that, in carriers of the apolipoprotein E (APOE) genotype ε3/ε3 or ε3/ε4, the presence of a very long (VL) polyT repeat allele in "translocase of outer mitochondrial membrane 40" (TOMM40) was less frequent in patients with sporadic inclusion body myositis (sIBM) compared with controls and associated with a later age of sIBM symptom onset, suggesting a protective effect of this haplotype. To further investigate the influence of these genetic factors in sIBM, we analyzed a large sIBM cohort of 158 cases as part of an International sIBM Genetics Study. No significant association was found between APOE or TOMM40 genotypes and the risk of developing sIBM. We found that the presence of at least 1 VL polyT repeat allele in TOMM40 was significantly associated with about 4 years later onset of sIBM symptoms. The age of onset was delayed by 5 years when the patients were also carriers of the APOE genotype ε3/ε3. In addition, males were likely to have a later age of onset than females. Therefore, the TOMM40 VL polyT repeat, although not influencing disease susceptibility, has a disease-modifying effect on sIBM, which can be enhanced by the APOE genotype ε3/ε3

Caspase-10: a molecular switch from cell-autonomous apoptosis to communal cell death in response to chemotherapeutic drug treatment.

The mechanisms of how chemotherapeutic drugs lead to cell cycle checkpoint regulation and DNA damage repair are well understood, but how such signals are transmitted to the cellular apoptosis machinery is less clear. We identified a novel apoptosis-inducing complex, we termed FADDosome, which is driven by ATR-dependent caspase-10 upregulation. During FADDosome-induced apoptosis, cFLIPL is ubiquitinated by TRAF2, leading to its degradation and subsequent FADD-dependent caspase-8 activation. Cancer cells lacking caspase-10, TRAF2 or ATR switch from this cell-autonomous suicide to a more effective, autocrine/paracrine mode of apoptosis initiated by a different complex, the FLIPosome. It leads to processing of cFLIPL to cFLIPp43, TNF-α production and consequently, contrary to the FADDosome, p53-independent apoptosis. Thus, targeting the molecular levers that switch between these mechanisms can increase efficacy of treatment and overcome resistance in cancer cells.Cell Death and Differentiation advance online publication, 3 November 2017; doi:10.1038/cdd.2017.164

Hereditary spastic paraplegia in Greece: characterisation of a previously unexplored population using next-generation sequencing

Hereditary Spastic Paraplegia (HSP) is a syndrome characterised by lower limb spasticity, occurring alone or in association with other neurological manifestations, such as cognitive impairment, seizures, ataxia or neuropathy. HSP occurs worldwide, with different populations having different frequencies of causative genes. The Greek population has not yet been characterised. The purpose of this study was to describe the clinical presentation and molecular epidemiology of the largest cohort of HSP in Greece, comprising 54 patients from 40 families. We used a targeted next-generation sequencing (NGS) approach to genetically assess a proband from each family. We made a genetic diagnosis in >50% of cases and identified 11 novel variants. Variants in SPAST and KIF5A were the most common causes of autosomal dominant HSP, whereas SPG11 and CYP7B1 were the most common cause of autosomal recessive HSP. We identified a novel variant in SPG11, which led to disease with later onset and may be unique to the Greek population and report the first nonsense mutation in KIF5A. Interestingly, the frequency of HSP mutations in the Greek population, which is relatively isolated, was very similar to other European populations. We confirm that NGS approaches are an efficient diagnostic tool and should be employed early in the assessment of HSP patients

Pilot phenotype and natural history study of hereditary neuropathies caused by mutations in the HSPB1 gene

Mutations in HSPB1 are one of the commonest causes of distal Hereditary Motor Neuropathy (dHMN). Transgenic mouse models of the disease have identified HDAC6 inhibitors as promising treatments for the condition paving the way for human trials. A detailed phenotype and natural history study of HSPB1 neuropathy is therefore required in order to inform the duration and outcome measures of any future trials. Clinical and neurophysiological data and lower limb muscle MRI were collected both prospectively and retrospectively from patients with mutations in HSPB1. The natural history was assessed by recording the weighted Charcot-Marie-Tooth Examination Score (CMTES) at annual intervals in a subset of patients. 20 patients from 14 families were recruited into the study. The average age of onset was in the 4th decade. Patients presented with a length dependent neuropathy but with early ankle plantar flexion weakness. Neurophysiology confirmed a motor neuropathy but also showed sensory nerve involvement in most patients. Cross sectional muscle MRI revealed soleus and medial gastrocnemius fat infiltration as an early signature of mutant HSPB1 disease. In this study neither semi quantitative muscle MRI, the CMTES nor neurophysiology were able to detect disease progression in HSPB1 neuropathy over 1 or 2 years. Further studies are therefore required to identify a suitable biomarker before clinical trials in HSPB1 neuropathy can be undertaken

Space Launch System Booster Separation Supersonic Powered Testing with Surface and Off-Body Measurements

A wind tunnel test was run in the NASA Langley Unitary Plan Wind Tunnel simulating the separation of the two solid rocket boosters (SRB) from the core stage of the NASA Space Launch System (SLS). The test was run on a 0.9% scale model of the SLS Block 1B Cargo (27005) configuration and the SLS Block 1B Crew (28005) configuration at a Mach of 4.0. High pressure air was used to simulate plumes from the booster separation motors located at the nose and aft skirt of the two boosters. Force and moment data were taken on both SRBs and on the core stage. Schlieren still photos and video were recorded throughout testing. A set of points were acquired using Cross-correlation Doppler Global Velocimetry (CCDGV) readings to get 3 component velocity measurements between the core and the left-hand SRB. The CCDGV laser was utilized to record flow visualization in the same location, between the core and the left-hand SRB. Pressure Sensitive Paint data were taken on a separate set of runs. Computational Fluid Dynamics (CFD) runs were computed on a subset of the wind tunnel data points for comparison. A combination of the force/moment, CCDGV and Pressure Sensitive Paint (PSP) data (as well as schlieren images) at the CFD-specified test conditions will be used te the CFD simulations that will be used to build an SLS booster separation database flight conditions

A de novo dominant mutation in KIF1A associated with axonal neuropathy, spasticity and autism spectrum disorder

Mutations in the kinesin family member 1A (KIF1A) gene have been associated with a wide range of phenotypes including recessive mutations causing hereditary sensory neuropathy and hereditary spastic paraplegia and de novo dominant mutations causing a more complex neurological disorder affecting both the central and peripheral nervous system. We identified by exome sequencing a de novo dominant missense variant, (c.38G>A, p.R13H), within an ATP binding site of the kinesin motor domain in a patient manifesting a complex phenotype characterized by autism spectrum disorder (ASD), spastic paraplegia and axonal neuropathy. The presence of ASD distinguishes this case from previously reported patients with de novo dominant mutations in KIF1A