Autosomal recessive colobomatous microphthalmia

Colobomatous microphthalmia was studied in multiple relatives of 5 families. In these families, the disorder was an autosomal recessive trait as opposed to the usual autosomal dominant form of the disorder. A relatively high incidence of this recessive allele is found in the Iranian Jewish community. © 1994 Wiley-Liss, Inc.     

Genetic mapping of a novel X-linked recessive colobomatous microphthalmia

Colobomatous microphthalmia is a common ocular malformation with a heterogeneous phenotype. The majority of cases without associated systemic abnormalities have an autosomal dominant inheritance pattern [McKusick, 1990: Mendelian inheritance in man]. A few isolated cases with autosomal recessive transmission have been described [Zlotogora et al., 1994: Am J Med Genet 49:261--262]. To our knowledge, no cases of X-linked colobomatous microphthalmia that are not a part of a syndrome or a multisystem disorder have been reported. In this study, we describe a genetic and clinical evaluation of a large pedigree in which colobomatous microphthalmia is segregating in an X-linked recessive fashion. Based on recombination breakpoint analysis, we have determined that the critical interval exists between markers DXS989 and DXS441, placing the disease locus on the proximal short arm or the proximal long arm of the X chromosome. Using linkage analysis, we obtained two-point lod scores of 2.71 at zero recombination with markers DXS1058, DXS6810, DXS1199, and DXS7132. Overlapping multipoint analysis established a broad maximum from marker DXS1068 to marker DXS7132, a region spanning approximately 28 cM. This study provides evidence for the presence of a new locus for colobomatous microphthalmia.     

An H3F3A K27M‐mutation in a sonic hedgehog medulloblastoma

Medulloblastomas are malignant embryonal brain tumours that may harbour mutations in histone‐modifying genes, while mutations in histone genes have not been detected to date. We here describe the first SHH medulloblastoma with H3 K27M mutation. This may have diagnostic implications as H3 K27M mutations are the hallmark of diffuse midline gliomas, H3 K27M mutant, WHO grade IV. Medulloblastomas arise in midline structures and thus must not be mistaken for DMG when using an antibody detecting the H3 K27M mutation.     

The sonic hedgehog signaling network in development and neoplasia

The sonic hedgehog (SHH) pathway was first defined genetically in fruit flies. Subsequently, the SHH network has been shown to be critical for normal mammalian development, by mediating interactions between stromal and epithelial cells. Recent evidence suggests that, deregulation of SHH signaling is important in the pathogenesis of cancer. Further, some observations suggest that a SHH paracrine mechanism mediating tumor-mesenchymal interactions may contribute to the metastatic capacity of cancer. Preclinical studies demonstrate that tumor cells in which SHH is deregulated are dependent on signaling through this pathway for the maintenance of proliferation and viability. SHH antagonists have been identified and show promise in inhibiting tumor growth in preclinical studies. The utility of these agents in the management of cancer patients awaits the outcome of ongoing and future clinical trials.     

Solitary median maxillary central incisor syndrome: clinical case with a novel mutation of sonic hedgehog

Solitary median maxillary central incisor (SMMCI) is a rare dental anomaly. It is usually considered as a minor manifestation of holoprosencephaly (HPE). Some reported families had severe cases of HPE in some members and SMMCI in others. Mutations of Sonic Hedgehog (SHH) have been documented in these families. SMMCI has also been found as an isolated finding or together with other anomalies such as microcephaly, short stature, endocrine pathology, and choanal atresia. We describe a patient with SMMCI and a novel SHH mutation: Val332Ala.     

Increased production of sonic hedgehog by ballooned hepatocytes

Ballooned hepatocytes distinguish non-alcoholic steatohepatitis (NASH) from steatosis. Such cells contain dilated endoplasmic reticulum and ubiquitin aggregates, characteristics of endoplasmic reticulum stress. Hepatocyte ballooning increases the risk for fibrosis in NASH, suggesting that ballooned hepatocytes release pro-fibrogenic factors. Hedgehog ligands function as pro-fibrogenic factors in liver diseases, but mechanisms for hedgehog ligand production remain poorly understood. We evaluated the hypothesis that endoplasmic reticulum stress induces hepatocyte production of hedgehog ligands that provide paracrine pro-fibrogenic signals to neighbouring cells. In livers from NASH patients, keratin 8/18 and ubiquitin staining demonstrated enlarged, keratin 8/18-negative/ubiquitin-positive hepatocytes (ballooned hepatocytes) that were positive for Sonic hedgehog. In order to model endoplasmic reticulum stress in vitro, primary mouse hepatocytes were treated with tunicamycin. Compared to vehicle, tunicamycin significantly increased Sonic hedgehog and Indian hedgehog expression. Furthermore, conditioned medium from tunicamycin-treated hepatocytes increased Gli-luciferase reporter activity 14-fold more than conditioned medium from vehicle-treated hepatocytes. Cyclopamine (hedgehog signalling inhibitor) abrogated the effect of conditioned medium from tunicamycin-treated hepatocytes, verifying that soluble hepatocyte-derived factors activate hedgehog signalling. Ballooned hepatocytes in NASH patients did not express the hedgehog target gene, Gli2, α-smooth muscle actin or vimentin, but were surrounded by Gli2-positive stromal cells expressing these myofibroblast markers. Trichrome staining demonstrated the accumulation of ballooned hepatocytes in areas of matrix deposition, and numbers of Sonic hedgehog-positive hepatocytes correlated with the degree of ballooning and fibrosis stage. Hepatocytes undergoing endoplasmic reticiulum stress generate hedgehog ligands which act as paracrine pro-fibrogenic factors for hedgehog-responsive stromal cells. These results help to explain why fibrosis stage correlates with hepatocyte ballooning in NASH.     

Sonic hedgehog信号通路调节痛觉敏化的研究进展

神经病理性痛是一种由于躯体感觉神经系统的损伤或疾病而直接造成的疼痛。Sonic hedgehog(Shh)信号转导通路是经典的控制胚胎发育的信号转导途径。近年来发现,该信号途径不仅参与胚胎神经系统模式发育,在成熟机体的稳态调节中也发挥重要作用,因此正逐渐成为信号转导领域新的研究热点。最新文献表明,Shh通路调节神经病理性疼痛的痛觉敏化,且其可能机制与星形胶质细胞激活,炎症因子以及突触可塑性的改变相关。     

Sonic hedgehog促1型糖尿病小鼠的伤口愈合

目的：研究sonic hedgehog（Shh）及其受体Ptc1在糖尿病小鼠伤口愈合中的作用。方法：分别在正常和链脲佐菌素（STZ）诱导的糖尿病小鼠建立皮肤损伤模型,Western印迹检测Shh和Ptc1的蛋白水平;观察外源性Shh或Ptc1抑制剂cyclopamine对伤口愈合的影响。结果：（1）正常小鼠损伤后皮肤组织中的Shh和Ptcl蛋白质表达明显升高;外源性Shh对伤口愈合无明显促进作用,但cyclopamine可以明显地抑制伤口愈合;（2）STZ诱导的糖尿病小鼠,其皮肤组织中内源性的Shh和Ptcl蛋白水平明显下调;（3）外源性Shh可显著促进糖尿病小鼠伤口的愈合,且呈浓度依赖性;Cyclopamine则明显地抑制糖尿病小鼠的伤口愈合。结论：Shh-Ptc1通路参与了皮肤伤口愈合,糖尿病伤口愈合延迟与Shh-Ptc1表达下调有关。     

Novel EDA mutation resulting in X-linked non-syndromic hypodontia and the pattern of EDA-associated isolated tooth agenesis

Familial non-syndromic hypodontia shows a wide phenotypic heterogeneity and inherits in an autosomal-dominant, autosomal-recessive or X-linked mode. Mutations in genes PAX9, MSX1 and AXIN2 have been determined to be associated with autosomal-dominant tooth agenesis. Recent studies in two families showed that X-linked non-syndromic hypodontia resulted from EDA mutations. In this study, a novel EDA mutation (Thr338Met) that results in X-linked non-syndromic hypodontia in a Chinese family was identified. The patterns of tooth agenesis in these related subjects with defined EDA mutation were analyzed using comparative statistical analysis of tooth agenesis in EDA, MSX1 and PAX9. Statistically significant differences (p < 0.001) were observed at eight positions. The resulting data of congenital absence of maxillary and mandibular central incisors, lateral incisors and canines, with the high possibility of persistence of maxillary and mandibular first permanent molars, appears as a pattern of tooth agenesis, suggesting the presence of an EDA mutation.     

Mathematical modelling of digit specification by a sonic hedgehog gradient

Background: The three chick wing digits represent a classical example of a pattern specified by a morphogen gradient. Here we have investigated whether a mathematical model of a Shh gradient can describe the specification of the identities of the three chick wing digits and if it can be applied to limbs with more digits. Results: We have produced a mathematical model for specification of chick wing digit identities by a Shh gradient that can be extended to the four digits of the chick leg with Shh‐producing cells forming a digit. This model cannot be extended to specify the five digits of the mouse limb. Conclusions: Our data suggest that the parameters of a classical‐type morphogen gradient are sufficient to specify the identities of three different digits. However, to specify more digit identities, this core mechanism has to be coupled to alternative processes, one being that in the chick leg and mouse limb, Shh‐producing cells give rise to digits; another that in the mouse limb, the cellular response to the Shh gradient adapts over time so that digit specification does not depend simply on Shh concentration. Developmental Dynamics 243:290–298, 2014. © 2013 Wiley Periodicals, Inc.     

Xenopus sonic hedgehog guides retinal axons along the optic tract

The role of classic morphogens such as Sonic hedgehog (Shh) as axon guidance cues has been reported in a variety of vertebrate organisms (Charron and Tessier‐Lavigne [ 2005 ] Development 132:2251–2262). In this work, we provide the first evidence that Xenopus sonic hedgehog (Xshh) signaling is involved in guiding retinal ganglion cell (RGC) axons along the optic tract. Xshh is expressed in the brain during retinal axon extension, adjacent to these axons in the ventral diencephalon. Retinal axons themselves express Patched 1 and Smoothened co‐receptors during RGC axon growth. Blocking Shh signaling causes abnormal ventral pathfinding, and targeting errors at the optic tectum. Misexpression of exogenous N‐Shh peptide in vivo also causes pathfinding errors. Retinal axons grown in culture respond to N‐Shh in a dose‐dependent manner, either by decreasing extension at lower concentrations, or retracting axons in the presence of higher doses. These data suggest that Shh signaling is required for normal RGC axon pathfinding and tectal targeting in the developing visual system of Xenopus. We propose that Shh serves as a ventral optic tract repellent that helps to define the caudal boundary for retinal axons in the diencephalon, and that this signaling is also required for initial target recognition at the optic tectum. Developmental Dynamics 239:2921–2932, 2010. © 2010 Wiley‐Liss, Inc.     

Homozygous null mutation in ODZ3 causes microphthalmia in humans

PurposeMicrophthalmia is a condition in which eyes are small in size, often associated with coloboma, as a result of aberrant eye development. Isolated microphthalmia is a model disease for studying early development of the human eye, and mutations in several key genes related to eye development have been linked to this phenotype.MethodsIn our search for novel genes that cause autosomal recessive microphthalmia when mutated, we enrolled a family that consists of third-cousin parents and two children with isolated colobomatous microphthalmia.ResultsExome and autozygome analysis identified a null mutation in ODZ3, one of four vertebrate orthologs of odz in Drosophila.ConclusionOur data highlight a role for ODZ3 in the early development of the human eye.Genet Med 2012:14(11):900–904