Bone-Like Mineral Nucleating Peptide Nanofibers Induce Differentiation of Human Mesenchymal Stem Cells into Mature Osteoblasts

Cataloged from PDF version of article.A bone implant should integrate to the tissue through a bone-like mineralized interface, which requires increased osteoblast activity at the implant-tissue boundary. Modification of the implant surface with synthetic bioinstructive cues facilitates on-site differentiation of progenitor stem cells to functional mature osteoblasts and results in subsequent mineralization. Inspired by the bioactive domains of the bone extracellular matrix proteins and the mussel adhesive proteins, we synthesized peptide nanofibers to promote bone-like mineralization on the implant surface. Nanofibers functionalized with osteoinductive collagen I derived Asp-Gly-Glu-Ala (DGEA) peptide sequence provide an advantage in initial adhesion, spreading, and early commitment to osteogenic differentiation for mesenchymal stem cells (hMSCs). In this study, we demonstrated that this early osteogenic commitment, however, does not necessarily guarantee a priority for maturation into functional osteoblasts. Similar to natural biological cascades, early commitment should be further supported with additional signals to provide a long-term effect on differentiation. Here, we showed that peptide nanofibers functionalized with Glu-Glu-Glu (EEE) sequence enhanced mineralization abilities due to osteoinductive properties for late-stage differentiation of hMSCs. Mussel-inspired functionalization not only enables robust immobilization on metal surfaces, but also improves bone-like mineralization under physiologically simulated conditions. The multifunctional osteoinductive peptide nanofiber biointerfaces presented here facilitate osseointegration for long-term clinical stability. © 2014 American Chemical Society

Characterization of a novel zebrafish (Danio rerio) gene, wdr81, associated with cerebellar ataxia, mental retardation and dysequilibrium syndrome (CAMRQ)

Background: WDR81 (WD repeat-containing protein 81) is associated with cerebellar ataxia, mental retardation and disequilibrium syndrome (CAMRQ2, [MIM 610185]). Human and mouse studies suggest that it might be a gene of importance during neurodevelopment. This study aimed at fully characterizing the structure of the wdr81 transcript, detecting the possible transcript variants and revealing its expression profile in zebrafish, a powerful model organism for studying development and disease. Results: As expected in human and mouse orthologous proteins, zebrafish wdr81 is predicted to possess a BEACH (Beige and Chediak-Higashi) domain, a major facilitator superfamily domain and WD40-repeats, which indicates a conserved function in these species. We observed that zebrafish wdr81 encodes one open reading frame while the transcript has one 5' untranslated region (UTR) and the prediction of the 3' UTR was mainly confirmed along with a detected insertion site in the embryo and adult brain. This insertion site was also found in testis, heart, liver, eye, tail and muscle, however, there was no amplicon in kidney, intestine and gills, which might be the result of possible alternative polyadenylation processes among tissues. The 5 and 18 hpf were critical timepoints of development regarding wdr81 expression. Furthermore, the signal of the RNA probe was stronger in the eye and brain at 18 and 48 hpf, then decreased at 72 hpf. Finally, expression of wdr81 was detected in the adult brain and eye tissues, including but not restricted to photoreceptors of the retina, presumptive Purkinje cells and some neurogenic brains regions. Conclusions: Taken together these data emphasize the importance of this gene during neurodevelopment and a possible role for neuronal proliferation. Our data provide a basis for further studies to fully understand the function of wdr81. © 2015 Doldur-Balli et al

Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

Cataloged from PDF version of article.Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebro-cerebellar structures required for posture and gait in humans. © 2013 Macmillan Publishers Limited All rights reserved

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features.

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities

Inherited predisposition to breast cancer in the Carolina Breast Cancer Study

The Carolina Breast Cancer Study (CBCS) phases I–II was a case-control study of biological and social risk factors for invasive breast cancer that enrolled cases and controls between 1993 and 1999. Case selection was population-based and stratified by ancestry and age at diagnosis. Controls were matched to cases by age, self-identified race, and neighborhood of residence. Sequencing genomic DNA from 1370 cases and 1635 controls yielded odds ratios (with 95% confidence limits) for breast cancer of all subtypes of 26.7 (3.59, 189.1) for BRCA1, 8.8 (3.44, 22.48) for BRCA2, and 9.0 (2.06, 39.60) for PALB2; and for triple-negative breast cancer (TNBC) of 55.0 (7.01, 431.4) for BRCA1, 12.1 (4.18, 35.12) for BRCA2, and 10.8 (1.97, 59.11) for PALB2. Overall, 5.6% of patients carried a pathogenic variant in BRCA1, BRCA2, PALB2, or TP53, the four most highly penetrant breast cancer genes. Analysis of cases by tumor subtype revealed the expected association of TNBC versus other tumor subtypes with BRCA1, and suggested a significant association between TNBC versus other tumor subtypes with BRCA2 or PALB2 among African-American (AA) patients [2.95 (1.18, 7.37)], but not among European-American (EA) patients [0.62 (0.18, 2.09)]. AA patients with pathogenic variants in BRCA2 or PALB2 were 11 times more likely to be diagnosed with TNBC versus another tumor subtype than were EA patients with pathogenic variants in either of these genes (P = 0.001). If this pattern is confirmed in other comparisons of similarly ascertained AA and EA breast cancer patients, it could in part explain the higher prevalence of TNBC among AA breast cancer patients

An Evolutionary Perspective on Complex Neuropsychiatric Disease

The forces of evolution-mutation, selection, migration, and genetic drift-shape the genetic architecture of human traits, including the genetic architecture of complex neuropsychiatric illnesses. Studying these illnesses in populations that are diverse in genetic ancestry, historical demography, and cultural history can reveal how evolutionary forces have guided adaptation over time and place. A fundamental truth of shared human biology is that an allele responsible for a disease in anyone, anywhere, reveals a gene critical to the normal biology underlying that condition in everyone, everywhere. Understanding the genetic causes of neuropsychiatric disease in the widest possible range of human populations thus yields the greatest possible range of insight into genes critical to human brain development. In this perspective, we explore some of the relationships between genes, adaptation, and history that can be illuminated by an evolutionary perspective on studies of complex neuropsychiatric disease in diverse populations

Genetics of schizophrenia in the South African Xhosa

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy