Autism and X-linked hypophosphatemia: A possible association?

We herein report the joint occurrence of an autistic disorder (AD) and X-linked hypophosphatemia. X-linked hypophosphatemia (XLH), an X-linked dominant disorder, is the most common of the inherited renal phosphate wasting disorders. Autism is a pervasive developmental disorder that occurs mainly due to genetic causes. In approximately 6-15% of cases, the autistic phenotype is a part of a broader genetic condition called syndromic autism.Therefore, reports of cases with the joint occurrence of a known genetic syndrome and a diagnosis of ASD by a child psychiatrist are relevant. A joint occurrence does not, however, mean that there is always a causal link between the genetic syndrome and the autistic behavioural phenotype. In this case, there are a number of arguments countering a causal link.     

Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency

X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency characterized by increased vulnerability to Epstein–Barr virus infection. XLP type 1 is caused by mutations in SH2D1A, whereas X-linked inhibitor of apoptosis (XIAP) encoded by XIAP/BIRC4 is mutated in XLP type 2. In XIAP deficiency, hemophagocytic lymphohistiocytosis (HLH) occurs more frequently and recurrence is common. However, the underlying mechanisms remain mostly unknown. We describe the characteristics of the cytokine profiles of serum samples from 10 XIAP-deficient patients. The concentration of interleukin (IL)-18 was strikingly elevated in the patients presented with HLH, and remained high after the recovery from HLH although levels of other pro-inflammatory cytokines approached the normal range. Longitudinal examination of two patients demonstrated marked exacerbation of IL-18 levels during every occasion of HLH. These findings may suggest the association between HLH susceptibility and high serum IL-18 levels in XIAP deficiency.     

Mineral tessellation in bone and the stenciling principle for extracellular matrix mineralization

We review here the Stenciling Principle for extracellular matrix mineralization that describes a double-negative process (inhibition of inhibitors) that promotes mineralization in bone and other mineralized tissues, whereas the default condition of inhibition alone prevents mineralization elsewhere in soft connective tissues. The stenciling principle acts across multiple levels from the macroscale (skeleton/dentition vs soft connective tissues), to the microscale (for example, entheses, and the tooth attachment complex where the soft periodontal ligament is situated between mineralized tooth cementum and mineralized alveolar bone), and to the mesoscale (mineral tessellation). It relates to both small-molecule (e.g. pyrophosphate) and protein (e.g. osteopontin) inhibitors of mineralization, and promoters (enzymes, e.g. TNAP, PHEX) that degrade the inhibitors to permit and regulate mineralization. In this process, an organizational motif for bone mineral arises that we call crossfibrillar mineral tessellation where mineral formations – called tesselles – geometrically approximate prolate ellipsoids and traverse multiple collagen fibrils (laterally). Tesselle growth is directed by the structural anisotropy of collagen, being spatially restrained in the shorter transverse tesselle dimensions (averaging 1.6 × 0.8 × 0.8 μm, aspect ratio 2, length range 1.5–2.5 μm). Temporo-spatially, the tesselles abut in 3D (close ellipsoid packing) to fill the volume of lamellar bone extracellular matrix. Poorly mineralized interfacial gaps between adjacent tesselles remain discernable even in mature lamellar bone. Tessellation of a same, small basic unit to form larger structural assemblies results in numerous 3D interfaces, allows dissipation of critical stresses, and enables fail-safe cyclic deformations. Incomplete tessellation in osteomalacia/odontomalacia may explain why soft osteomalacic bones buckle and deform under loading.     

Peripartum Ca and P homeostasis in multiparous sows fed adequate or excess dietary Ca

The recent increased prevalence of uterine prolapses in sows around parturition has led to inferences that the prolapses may be associated with hypocalcemia. However, limited data are available to support that hypocalcemia occurs in sows. Hypocalcemia in dairy cows is associated with feeding excess dietary Ca during late gestation. The excess Ca is assumed to suppress homeostatic mechanisms critical to maintain serum Ca concentrations as the Ca demand increases during the early stages of lactation. In this experiment, sows were fed diets with excess Ca during late gestation and early lactation to assess the potential development of hypocalcemia in the peripartum period. Twelve crossbred (Large White × Landrace) multiparous gestating sows were fed a control diet (CON), 0.65% Ca to 0.38% standardized total tract digestible P (STTD P) and 0.67% Ca to 0.38% STTD P in gestation and lactation diets, respectively) or a high Ca diet (HCa, 1.75% Ca to 0.46% STTD P and 1.75% Ca to 0.45% STTD P in gestation and lactation diets, respectively). The diets were fed from gestation day 86 þ ± 1 until the end of lactation (27 þ ± 2 days period). On day 112 of gestation, indwelling venous catheters were placed in each sow. Blood samples were collected at 15-min intervals within four designated times (0700, 1000, 1300 and 1700 h) on gestation day 113 and lactation days 1, 3 and 5. Venous blood pH, gases (pO₂, pCO₂ and HCO₃⁻), electrolytes (K⁺, Na⁺ and Cl⁻), ionized Ca (iCa), metabolites (glucose and lactate), plasma total Ca (tCa), and P were analyzed. Overall, sows fed HCa diet had greater (P < 0.001) concentrations of blood iCa and plasma tCa than sows fed CON diets. No clinical signs of Ca metabolism disorders were observed. Unexpectedly, concentrations of plasma P in sows fed HCa diets were lower (P < 0.001) than in sows fed CON diets. Plasma P tended to decrease (P = 0.057) as day of lactation increased. Differences between dietary treatments for blood pH, gases, electrolytes and metabolites were not detected (P > 0.05). No evidence for hypocalcemia was detected in peripartum sows fed CON or HCa diets. These data imply that excess Ca in late gestation diets did not result in hypocalcemia during the peripartum period. Future experiments should focus on factors other than hypocalcemia to identify causes of uterine prolapses in sows.     

X连锁凋亡抑制蛋白的功能及其在肿瘤中的作用

X连锁凋亡抑制蛋白(X-linked inhibitor of apoptosis,XIAP)是目前发现的最具特征性与作用最强的内源性凋亡抑制蛋白质.XIAP特征性结构是其BIR结构域和RING结构域,它们都是XIAP发挥抗凋亡作用的重要结构.多种内源性抑制蛋白质(XAF1、Smac和Omi)能通过不同的方式抑制XIA...     

dXNP, a Drosophila homolog of XNP/ATRX, induces apoptosis via Jun-N-terminal kinase activation

XNP/ATRX, a causative gene of X-linked alpha-thalassemia/mental retardation syndrome, encodes an SNF2 family ATPase/helicase protein. To better understand the role of XNP/ATRX in development, we isolated and characterized a Drosophila XNP/ATRX homolog, dXNP, which contains highly conserved SNF2 and helicase domains. Ectopically expressed dXNP induced strong apoptosis in the developing eye and wing, but did not affect cell cycle progression or the expression of wingless and engrailed, essential regulators of development. The dXNP-induced apoptosis was strongly suppressed by DJNKK/hemipterous mutation, and dXNP increased JNK activity. Taken together, these results suggest that dXNP regulates apoptosis via JNK activation.     

Bex蛋白家族的研究进展

Bex家族(brain expressed,X-linked gene family)是X染色体连锁基因家族,虽然蛋白分子量只有120aa左右,但却包含了入核信号序列、出核信号基序、CAAX膜锚定序列等多个功能结构域,这些结构域的存在决定了Bex分子可以在亚细胞的不同部位间穿梭,执行不同的信号转导和生理功能。目前很多研究报导了Bex参与机体的发育与分化、细胞凋亡与肿瘤形成等重要的生理和病理过程,提示这类小分子蛋白家族可能扮演了重要的在体功能的角色。虽然人的Bex基因由我国学者首次发现,但国内有关Bex家族的研究工作和相关的理论参考均不多见。本文拟就Bex家族迄今为止突出的研究进展作一综述,旨在为下一步的功能研究工作提供理论参考和依据。     

Interaction of an Amphiphilic Peptide with a Phospholipid Bilayer Surface by Molecular Dynamics Simulation Study

Abstract

Corticotropin-releasing factor (CRF) is the principal neuroregulator of adrenocorticotropic hormone (ACTH) secretion. Previous experiments have demonstrated that CRF binds avidly to the surface of single egg phosphatidylcholine vesicles and its amphiphilic secondary structure might play an important role in the function. In this study, the interaction of the residues 13–41 in human CRF with the surface of a DOPC bilayer was investigated by molecular dynamics (MD) simulation in order to understand the role of the membrane surface in the formation of the amphiphilic α helix as well as to determine the effects of the peptide on the lipid bilayer. The model used included 60 DOPC molecules, 1 helical peptide (CRF_13–41) on the bilayer surface, and explicit waters of solvation in the lipid polar head group regions, together with constant-volume periodic boundary conditions in three dimensions. The MD simulation was carried out for 510 ps. In addition, CRF_13–41, initially in a helical form, was simulated in vacuo as a control. The results indicate that while it was completely unstable in vacuo, the peptide helical form was generally maintained on the bilayer surface, but with distortions near the terminal ends. The peptide was confined to the bilayer headgroup/water region, similar to that reported from neutron diffraction measurement of tripeptides bound to the phosphatidylcholine bilayer surface (Ref 1). The amphiphilicity of the peptide matched that of the bilayer headgroup environment, with the hydrophilic side oriented toward water and the hydrophobic side making contact with the bilayer hydrocarbon core. These results support the hypothesis that the amphiphilic environment of a membrane surface is important in the induction of peptide amphiphilic α-helical secondary structure. Two major effects of the peptide on the lipids were found: the first CH₂ segment in the lipid chains was significantly disordered and the lipid headgroup distribution was broadened towards the water region.     

XIAP 基因在肿瘤中的研究进展

XIAP(X链锁凋亡抑制蛋白,X-linked inhibitor-of-apoptosis protain)是凋亡抑制蛋白(IAPs)家族中最有效力的caspase抑制物,具有抑制细胞凋亡,参与肿瘤的发生、发展。本文就XIAP在肿瘤中的作用机制、表达及治疗情况做一综述,有望为肿瘤的诊断及治疗提供一个新方法。     

Intact Fibroblast Growth Factor 23 Concentrations in Hypophosphatemic Disorders

ObjectiveEvaluation of circulating fibroblast growth factor 23 (FGF23) concentrations plays a key role in the differential diagnosis of patients presenting with hypophosphatemia. FGF23 concentrations obtained by different immunoassays are not comparable and subsequently, differences in the clinical performance of the assays might arise. In this study, we evaluated the clinical performance of the Medfrontier FGF23 Intact immunoassay (MedFrontier, Minaris Medical Co, Ltd, Tokyo, Japan) in clinically relevant hypophosphatemic conditions.MethodsIntact FGF23 (iFGF23) was measured in serum samples from 61 patients with FGF23-dependent hypophosphatemia (42-tumor induced osteomalacia [TIO] and 19-X-linked hypophosphatemia [XLH]); 8 patients with FGF23-independent hypophosphatemia (6-Fanconi Syndrome and 2-Vitamin D dependent rickets); 10 normophosphatemic patients; 15 chronic kidney disease (CKD) stage-2/3 and 20 CKD stage-4/5 patients; and a healthy control population. Disease-specific differences in measured iFGF23 concentrations and FGF23 concentration association with phosphate concentrations were reported.ResultsiFGF23 concentrations were significantly elevated in 90% and 84% of TIO and XLH hypophosphatemia patients as compared to healthy controls (both TIO and XLH, P = .0001). There was no significant correlation between iFGF23 and phosphate concentrations (P = .74 and P = .86) for TIO and XLH, respectively. Patients with CKD showed a significant increase in serum iFGF23 as the estimated glomerular filtration rate decreased (ρ = -0.79, P ≤ 0.0001).ConclusionsThis study evaluated the clinical performance of the MedFrontier iFGF23 assay in a large cohort of XLH and TIO Caucasian and Asian patients. The clinical sensitivity of this iFGF23 assay is appropriate for clinical use.     

X-linked recessive combined pituitary hormone deficiency is mapped to Xp22.3-Xp11 in a Chinese family

Genetic mutations have been identified in a modest proportion of patients with combined pituitary hormone deficiency (CPHD). We reported a 3-generation family consisting of 18 members, including 5 affected males (the proband, his 2 brothers, his cousin, and his maternal uncle; III1–III4, II8) suffered with CPHD. MRI of the pituitary gland showed hypoplasia of the pituitary gland in affected members. By 19 STR markers and linkage analysis, we found that the disease gene localized between the DXS987 and DXS1226 markers (LOD score = 2.408, θ = 0). All affected male patients inherited the same haplotype from the female carrier (I4). The proband's mother (II4) and her sister (II3, II6) were obligate female carriers. However, the unaffected males (II₇, II₉) in the family did not have this haplotype. These observations confirm a new X-linked recessive inherited disease in a Chinese family with CPHD and the pathogenic gene is mapped to Xp22.1–Xp11.     

Prognostic significance of X-linked inhibitor of apoptosis protein in solid tumors: A systematic review and meta-analysis

X-linked inhibitor of apoptosis protein (XIAP) is aberrantly expressed in solid tumors. Considering conflicting data, we conducted this meta-analysis to investigate its prognostic role. Electronic databases were searched to collect studies about associations between XIAP expressions and survival outcomes. Hazard ratio (HR), odds ratio (OR), and 95% confidence interval (CI) were utilized as effect size estimates. A total of 3,794 patients from 21 published studies were included. The results revealed that high XIAP expressions correlated with age (OR = 2.02; 95% CI, 1.07–3.84), lymph node metastasis (OR = 1.69; 95% CI, 1.02–2.77), histological grade (OR = 2.04; 95% CI, 1.01–4.11), and tumor stage (OR = 2.18; 95% CI, 1.20–3.96). The combined HR revealed that high XIAP expressions associated with poor overall survival (OS) (HR = 1.60; 95% CI, 1.22–2.10). Our study suggested high XIAP expressions may be indicative of poor prognosis in solid tumors.     

Human thyroxine-binding globulin (TBG): Heterogeneity within individuals and among individuals demonstrated by isoelectric focusing

Isoelectric focusing of human plasma samples labeled in vitro with [¹²⁵I]-thyroxine reveals considerable biochemical and genetic variation in thyroxine-binding globulin. (1) In all individuals tested, at least three primary isoelectric bands are seen in the pH range of 4.2 to 4.5, with additional bands at lower pH ranges. Similar patterns are produced by plasma from nonhuman primates. These band differences appear to be the result of differences in sialic acid content. TBG produces a single electrophoretic band on standard polyacrylamide gel electrophoresis. (2) Genetically determined, X-linked differences in electrophoretic mobility of TBG are observed in several human populations. Female homozygotes or male hemizygotes for the TBG slow variant (TBG-S) produce band patterns shifted by 0.5 pH unit cathodal to the common pattern (TBG-C). Female heterozygotes produce patterns with six-plus bands, representing the simple sum of the common and slow types. This difference is not the result of differences in sialic acid content. The gene frequency of this variant is 10% in American Blacks. (3) In pregnant women additional anodal bands are observed, giving the impression of a shift, by integral steps, in the pattern relative to the nonpregnant type. This shift is abolished by mild neuraminidase treatment.This work was supported by a grant from the O'Brien family of Houston, Texas.     

过氧化物酶体的生物发生与疾病

过氧化物酶体的膜蛋白和酶分子由核基因编码,在游离的核糖体上合成之后,由定位信号引导靶向运输并组装到过氧化物酶体的。本文就过氧化物酶体膜蛋白信号ｍＰＴＳ、酶分子信号ＰＴＳ１Ｔ ＰＴＳ２、酶分子运进过氧化物酶体的模型以及由于过氧化物酶体生物发生的障碍而引起的疾病加以讨论。     

Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP

Here we demonstrate that JNK3 can phosphorylate Smac. Smac phosphorylation attenuates its ability to activate apoptosome activity in HeLa S-100 cell lysates. Addition of the X-linked inhibitor of apoptosis protein (XIAP) to the S-100 markedly suppresses apoptosome activity, and this suppressive effect of XIAP is neutralized by adding unphosphorylated Smac, but not phosphorylated Smac. Furtherover, JNK3-mediated phosphorylation of Smac markedly attenuates the interaction between Smac and XIAP, as measured by BIACORE assays and non-denaturing gel shift assays. When JNK3 activity is down-regulated in etoposide-induced HeLa cells by transiently overexpressing a dominant negative version of JNK3 (DN-JNK3), the caspase-3 activity as well as PARP cleavages are markedly enhanced. And the interaction of Smac with XIAP also increases by down-regulating JNK3 activity under the same conditions. These results suggest that JNK3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between Smac and XIAP.     

Osteocytes but not osteoblasts directly build mineralized bone structures

Bone-forming osteoblasts have been a cornerstone of bone biology for more than a century. Most research toward bone biology and bone diseases center on osteoblasts. Overlooked are the 90% of bone cells, called osteocytes. This study aims to test the hypothesis that osteocytes but not osteoblasts directly build mineralized bone structures, and that defects in osteocytes lead to the onset of hypophosphatemia rickets. The hypothesis was tested by developing and modifying multiple imaging techniques, including both in vivo and in vitro models plus two types of hypophosphatemia rickets models (Dmp1-null and Hyp, Phex mutation mice), and Dmp1-Cre induced high level of β-catenin models. Our key findings were that osteocytes (not osteoblasts) build bone similar to the construction of a high-rise building, with a wire mesh frame (i.e., osteocyte dendrites) and cement (mineral matrices secreted from osteocytes), which is a lengthy and slow process whose mineralization direction is from the inside toward the outside. When osteoblasts fail to differentiate into osteocytes but remain highly active in Dmp-1-null or Hyp mice, aberrant and poor bone mineralization occurs, caused by a sharp increase in Wnt-β-catenin signaling. Further, the constitutive expression of β-catenin in osteocytes recaptures a similar osteomalacia phenotype as shown in Dmp1 null or Hyp mice. Thus, we conclude that osteocytes directly build bone, and osteoblasts with a short life span serve as a precursor to osteocytes, which challenges the existing dogma.     

Mutational analysis of X-linked adrenoleukodystrophy gene

X-linked adrenoleukodystrophy (ALD) is an inherited peroxisomal disorder characterized by progressive neurological dysfunction, occasionally associated with adrenal insufficiency. The clinical thenotypes of ALD are quite variable, and include childhood ALD, adult-onset ALD, adrenomyeloneuropathy, and Addison's disease only. Although the causative gene for ALD has been identified, the physiological role of the gene product remains to be clarified. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified. The authors investigated genotype-phenotype correlatons in ALD by analyses on 29 unrelated Japanese patients with ALD and by a review of the literature. All the phenotypes were associated with mutations leading to protein truncation, as well as those resulting in subtle amino acid changes. Furthermore, there were no differences in phenotypic expression among the natures of the subtle amino acid changes. All these data indicate that no obvious correlations exist between the phenotypes of ALD patients and their geneotypes, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD.     

Postmating-prezygotic isolation is not an important source of selection for reinforcement within and between species in Drosophila pseudoobscura and D. persimilis

Abstract Most work on adaptive speciation to date has focused on the role of low hybrid fitness as the force driving reinforcement (the evolution of premating isolation after secondary contact that reduces the likelihood of matings between populations). However, recent theoretical work has shown that postmating, prezygotic incompatibilities may also be important in driving premating isolation. We quantified premating, postmating-prezygotic, and early postzygotic fitness effects in crosses among three populations: Drosophila persimilis, D. pseudoobscura USA (sympatric to D. persimilis ), and D. pseudoobscura Bogotá (allopatric to D. persimilis ). Interspecific matings were more likely to fail when they involved the sympatric populations than when they involved the allopatric populations, consistent with reinforcement. We also found that failure rate in sympatric mating trials depended on whether D. persimilis females were paired with D. pseudoobscura males or the reverse. This asymmetry most likely indicates differences in discrimination against heterospecific males by females. By measuring egg laying rate, fertilization success and hatching success, we also compared components of postmating-prezygotic and early postzygotic isolation. Postmating-prezygotic fitness costs were small and not distinguishable between hetero- and conspecific crosses. Early postzygotic fitness effects due to hatching success differences were also small in between-population crosses. There was, however, a postzygotic fitness effect that may have resulted from an X-linked allele found in one of the two strains of D. pseudoobscura USA. We conclude that the postmating-prezygotic fitness costs we measured probably did not drive premating isolation in these species. Premating isolation is most likely driven in sympatric populations by previously known hybrid male sterility.     

Localization of two new X-linked quantitative trait loci controlling corpus callosum size in the mouse

Corpus callosum (CC) size is a complex trait, characterized by a gradation of values within a normal range, as well as abnormalities that include a small or totally absent CC. Among inbred mouse strains with defects of the CC, BTBR T(+)tf/J (BTBR) mice have the most extreme phenotype; all animals show total absence of the CC and severe reduction of the hippocampal commissure (HC). In contrast, the BALB/cByJ (BALB) strain has a low frequency of small CC and consistently normal HC. Reciprocal F(1) crosses between BTBR and BALB suggest the presence of X-linked quantitative trait loci (QTLs) affecting CC size. Through linkage analysis of backcross male progeny, we have localized two regions on the X chromosome, having peaks at 68.5 Mb (approximately 29.5 cM) and at 134.5 Mb (approximately 60.5 cM) that are largely responsible for the reciprocal differences, with the BTBR allele showing X-linked dominant inheritance associated with CC defects.