DOCK6 mutations are responsible for a distinct autosomal-recessive variant of Adams-Oliver syndrome associated with brain and eye anomalies.

Adams-Oliver syndrome (AOS) is characterized by the association of aplasia cutis congenita with terminal transverse limb defects, often accompanied by additional cardiovascular or neurological features. Both autosomal-dominant and autosomal-recessive disease transmission have been observed, with recent gene discoveries indicating extensive genetic heterogeneity. Mutations of the DOCK6 gene were first described in autosomal-recessive cases of AOS and only five DOCK6-related families have been reported to date. Recently, a second type of autosomal-recessive AOS has been attributed to EOGT mutations in three consanguineous families. Here, we describe the identification of 13 DOCK6 mutations, the majority of which are novel, across 10 unrelated individuals from a large cohort comprising 47 sporadic cases and 31 AOS pedigrees suggestive of autosomal-recessive inheritance. DOCK6 mutations were strongly associated with structural brain abnormalities, ocular anomalies, and intellectual disability, thus suggesting that DOCK6-linked disease represents a variant of AOS with a particularly poor prognosis.

DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies.

The original article to which this Erratum refers was published in Human Mutation 36(6):593­598(DOI:10.1002/humu22795).The authors realized that a co-author, Nuria C. Bramswig, was left off of the title page of this article at the time of submission. This erratum serves to correct this error by including Dr. Bramswig and Dr. Bramswig's institution in the title page information.The authors regret the error.

Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huët anomaly).

Pelger-Huët anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape.

A geospatial platform for the tectonic interpretation of low-temperature thermochronology Big Data.

Low-temperature thermochronology is a powerful tool for constraining the thermal evolution of rocks and minerals in relation to a breadth of tectonic, geodynamic, landscape evolution, and natural resource formation processes through deep time. However, complexities inherent to these analytical techniques can make interpreting the significance of results challenging, requiring them to be placed in their geological context in 4-dimensions (3D + time). We present a novel tool for the geospatial archival, analysis and dissemination of fission-track and (U-Th)/He data, built as an extension to the open-access AusGeochem platform ( https://ausgeochem.auscope.org.au ) and freely accessible to scientists from around the world. To demonstrate the power of the platform, three regional datasets from Kenya, Australia and the Red Sea are placed in their 4D geological, geochemical, and geographic contexts, revealing insights into the tectono-thermal evolutions of these areas. Beyond facilitating data interpretation, the archival of fission track and (U-Th)/He (meta-)data in relational schemas unlocks future potential for greater integration of thermochronology and numerical geoscience techniques. The power of formatting data to interface with external tools is demonstrated through the integration of GPlates Web Service with AusGeochem, enabling thermochronology data to be readily viewed in their paleogeographic context through deep time from within the platform.

Wiedemann-Steiner syndrome: three further cases.

We describe three patients with a syndrome comprising arched, thick eyebrows, hypertelorism, narrow palpebral fissures, broad nasal bridge and tip, long philtrum, thin upper lip, stubby hands and feet, hirsutism, and severe psychomotor retardation. These patients expand the phenotype of the Wiedemann-Steiner syndrome and delineate it as an entity.

Additional clinical and molecular analyses of TFAP2A in patients with the branchio-oculo-facial syndrome.

The branchio-oculo-facial syndrome (BOFS) is a rare disorder with approximately 50 sporadic and familial cases in the literature. We report on the clinical and molecular analyses of five additional patients with BOFS (two familial and three sporadic). DNA analysis of the TFAP2A gene associated with BOFS using DNA sequencing detected a mutation [c.763A>G (p.Arg255Gly)] in two unrelated patients. This mutation had been reported in another patient and indicates a probable mutational hotspot in the TFAP2A gene. We also detected three new mutations which are restricted to exons 4-6. These gene regions are almost free of any single nucleotide polymorphisms. An evolutionary sequence comparison showed a high degree of sequence conservation from humans to the honey bee (Apis mellifera) in exon 6 showing that this part of the protein is probably essential. Our study represents the second group of BOFS patients with molecular confirmation, expanding the phenotype and spectrum of mutations and limiting it to a restricted part of the gene.

Calcium phosphate coating of nickel-titanium shape-memory alloys. Coating procedure and adherence of leukocytes and platelets.

Nickel-titanium shape-memory alloys (NiTi-SMA) were coated with calcium phosphate by dipping in oversaturated calcium phosphate solution. The layer thickness (typically 5-20 micrometer) can be varied by choice of the immersion time. The porous nature of the layer of microcrystals makes it mechanically stable enough to withstand both the shape-memory transition upon cooling and heating and also strong bending of the material (superelastic effect). This layer may improve the biocompatibility of NiTi-SMA, particulary for osteosynthetic devices by creating a more physiological surface and by restricting a potential nickel release. The adherence of human leukocytes (peripheral blood mononuclear cells and polymorphonuclear neutrophil granulocytes) and platelets to the calcium phosphate layer was analyzed in vitro. In comparison to non-coated NiTi-SMA, leukocytes and platelets showed a significantly increased adhesion to the coated NiTi-SMA.

Easy assessment of the biocompatibility of Ni-Ti alloys by in vitro cell culture experiments on a functionally graded Ni-NiTi-Ti material.

The biocompatibility of nickel-titanium alloys was investigated by single-culture experiments on functionally graded samples with a stepwise change in composition from pure nickel to pure titanium, including an Ni-Ti shape memory alloy for a 50:50 mixture. This approach permitted a considerable decrease of experimental resources by simultaneously studying a full variation of composition. The results indicate a good biocompatibility for a nickel content up to about 50%. The cells used in the biocompatibility studies comprised osteoblast-like osteosarcoma cells (SAOS-2, MG-63), primary human osteoblasts (HOB), and murine fibroblasts (3T3).

Impaired epidermal ceramide synthesis causes autosomal recessive congenital ichthyosis and reveals the importance of ceramide acyl chain length.

The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.

Goltz-Gorlin (focal dermal hypoplasia) and the microphthalmia with linear skin defects (MLS) syndrome: no evidence of genetic overlap.

Focal dermal hypoplasia (FDH) is an X-linked developmental disorder with male lethality characterized by patchy dermal hypoplasia, skeletal and dental malformations, and microphthalmia or anophthalmia. Recently, heterozygous loss-of-function mutations in the PORCN gene have been described to cause FDH. FDH shows some clinical overlap with the microphthalmia with linear skin defects (MLS) syndrome, another X-linked male lethal condition, associated with mutations of HCCS in the majority of cases. We performed DNA sequencing of PORCN in 13 female patients with the clinical diagnosis of FDH as well as four female patients with MLS syndrome and no mutation in HCCS. We identified PORCN mutations in all female patients with FDH. Eleven patients seem to have constitutional PORCN alterations in the heterozygous state and two individuals are mosaic for the heterozygous sequence change in PORCN. No PORCN mutation was identified in the MLS-affected patients, providing further evidence that FDH and MLS do not overlap genetically. X chromosome inactivation (XCI) analysis revealed a random or slightly skewed XCI pattern in leukocytes of individuals with intragenic PORCN mutation suggesting that defective PORCN does not lead to selective growth disadvantage, at least in leukocytes. We conclude that the PORCN mutation detection rate is high in individuals with a clear-cut FDH phenotype and somatic mosaicism can be present in a significant proportion of patients with mild or classic FDH.

Toward a holistic and risk-based management of European river basins.

The European Union Water Framework Directive (WFD) requires a good chemical and ecological status of European surface waters by 2015. Integrated, risk-based management of river basins is presumed to be an appropriate approach to achieve that goal. The approach of focusing on distinct hazardous substances in surface waters together with investment in best available technology for treatment of industrial and domestic effluents was successful in significantly reducing excessive contamination of several European river basins. The use of the concept of chemical status in the WFD is based on this experience and focuses on chemicals for which there is a general agreement that they should be phased out. However, the chemical status, based primarily on a list of 33 priority substances and 8 priority hazardous substances, considers only a small portion of possible toxicants and does not address all causes of ecotoxicological stress in general. Recommendations for further development of this concept are 1) to focus on river basin-specific toxicants, 2) to regularly update priority lists with a focus on emerging toxicants, 3) to consider state-of-the-art mixture toxicity concepts and bioavailability to link chemical and ecological status, and 4) to add a short list of priority effects and to develop environmental quality standards for these effects. The ecological status reflected by ecological quality ratios is a leading principle of the WFD. While on the European scale the improvement of hydromorphological conditions and control of eutrophication are crucial to achieve a good ecological status, on a local and regional scale managers have to deal with multiple pressures. On this scale, toxic pollution may play an important role. Strategic research is necessary 1) to identify dominant pressures, 2) to predict multistressor effects, 3) to develop stressor- and type-specific metrics of pressures, and 4) to better understand the ecology of recovery. The concept of reference conditions to define the ecological status is hard to apply and tends to ignore the fact that ecosystems can be highly dynamic. A better understanding of ecosystem responses to changes as well as early warning systems and concepts sensitive to various stressors to discriminate disturbances from natural variation are required. Because ecosystems are closely interconnected, an integrated monitoring, diagnosis, and stressors-based management of the whole water, sediment, groundwater, soil, and air system is required considering land use and the interaction with a changing climate. Extending this holistic approach beyond a consideration of existing pressures by anticipating on future ones to use and protect the aquatic environment in a sustainable way is one of the big challenges.

Gerodermia osteodysplastica is caused by mutations in SCYL1BP1, a Rab-6 interacting golgin.

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.

Severely incapacitating mutations in patients with extreme short stature identify RNA-processing endoribonuclease RMRP as an essential cell growth regulator.

The growth of an individual is deeply influenced by the regulation of cell growth and division, both of which also contribute to a wide variety of pathological conditions, including cancer, diabetes, and inflammation. To identify a major regulator of human growth, we performed positional cloning in an autosomal recessive type of profound short stature, anauxetic dysplasia. Homozygosity mapping led to the identification of novel mutations in the RMRP gene, which was previously known to cause two milder types of short stature with susceptibility to cancer, cartilage hair hypoplasia, and metaphyseal dysplasia without hypotrichosis. We show that different RMRP gene mutations lead to decreased cell growth by impairing ribosomal assembly and by altering cyclin-dependent cell cycle regulation. Clinical heterogeneity is explained by a correlation between the level and type of functional impairment in vitro and the severity of short stature or predisposition to cancer. Whereas the cartilage hair hypoplasia founder mutation affects both pathways intermediately, anauxetic dysplasia mutations do not affect B-cyclin messenger RNA (mRNA) levels but do severely incapacitate ribosomal assembly via defective endonucleolytic cleavage. Anauxetic dysplasia mutations thus lead to poor processing of ribosomal RNA while allowing normal mRNA processing and, therefore, genetically separate the different functions of RNase MRP.

Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis.

The Shprintzen-Goldberg syndrome (SGS) is a disorder of unknown cause comprising craniosynostosis, a marfanoid habitus and skeletal, neurological, cardiovascular, and connective-tissue anomalies. There are no pathognomonic signs of SGS and diagnosis depends on recognition of a characteristic combination of anomalies. Here, we describe 14 persons with SGS and compare their clinical findings with those of 23 previously reported individuals, including two families with more than one affected individual. Our analysis suggests that there is a characteristic facial appearance, with more than two thirds of all individuals having hypertelorism, down-slanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears. Other commonly reported manifestations include hypotonia in at least the neonatal period, developmental delay, and inguinal or umbilical hernia. The degree of reported intellectual impairment ranges from mild to severe. The most common skeletal manifestations in SGS were arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility. None of the skeletal signs alone is specific for SGS. Our study includes 14 mainly German individuals with SGS evaluated over a period of 10 years. Given that only 23 other persons with SGS have been reported to date worldwide, we suggest that SGS may be more common than previously assumed.

Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.

Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes. We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25. This interval includes the gene bone morphogenetic protein receptor 1B (BMPR1B), a type I transmembrane serinethreonine kinase. In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor. In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain. An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism. Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors. Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb. These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner.