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Objective To identify causative genetic mutations by targeted exome sequencing in 9 independent pedigrees with familial exudative vitreoretinopathy (FEVR) and characterize the novel pathogenic mutations by molecular dynamics simulation. Methods Clinical data were collected from 9 families with FEVR. The causative genes were screened by targeted next-generation sequencing (TGS) and verified by the Sanger sequencing. In silico analyses (SIFT, Polyphen2, Revel, Mutation taster, and GERP++) were carried out to evaluate the pathogenicity of the mutations. Molecular dynamics was simulated to predict the alterations of protein conformation and flexibility transformation on pathogenesis. Results A 44% overall detection rate was achieved with four mutations including c.4289delC:p.Pro1431Argfs*8, c.2073G > T:p.Trp691Cys, c.1801G > A:p.Gly601Arg in LRP5 and c.633T > A:p.Tyr211* in TSPAN12 in 4 unrelated probands. Based on in silico analysis and ACMG standard, two of them, c.4289delC:p.Pro1431Argfs*8 and c.2073G > T:p.Trp691Cys of LRP5 were identified as novel pathogenic mutations. According to a molecular dynamics simulation, both mutations altered the secondary structure and spatial conformation, thus compromising its stability and flexibility. Conclusion Two novel genetic variants of the LRP5 gene were found to contribute to FEVR in this study, enriching the mutation spectrum of this condition. The impact of these two mutations on protein structure was validated by molecular dynamics simulation, further evidencing their pathogenicity.

Background: The rs1401999 gene in ABCC5 gene was the first locus confirmed by a genome-wide association study (GWAS) to be associated with both anterior chamber depth (ACD) and primary angle closure glaucoma (PACG); however, this locus was of obvious heterogeneity among different populations in the GWAS, and the conclusion has not been further verified by other studies. Therefore, this study was carried out to investigate whether the single-nucleotide polymorphisms (SNPs) in ABCC5 gene are associated with PACG and the ocular biometric parameters ACD and axial length (AL) in samples from northern China. Methods: Case-control association study included 500 PACG patients and 720 unrelated controls from northern China, and genotyping was performed for ten SNPs in ABCC5 gene using an improved multiplex ligation detection reaction technique. The association between these SNPs and risk of PACG was estimated by PLINK using a logistic regression model, while the association between genotypes and ocular biometric parameters was performed by SPSS using generalized estimation equation. Results: An SNP rs4148568 (p = 0.046) and a haplotype TCGGAG (p = 0.0364) in ABCC5 were associated with PACG, and rs4148568 was nominally associated with AL (β = 0.092, p = 0.08). Conclusions: The SNP rs4148568 and a haplotype TCGGAG in ABCC5 contribute to PACG in northern Chinese people. In addition, rs4148568 might be associated with the AL, the variant allele of which may have effect of making the AL longer. Further studies are needed to elucidate the exact mechanism of ABCC5 in the progress of PACG.

AIM: To investigate whether the gene variants in MYOC and ABCA1 are associated with primary angle-closure glaucoma (PACG) and anterior chamber depth (ACD) and axial length (AL) in samples from northern China. METHODS: The present case-control association study consisted of 500 PACG patients and 720 unrelated controls. Each participant was genotyped for eleven single nucleotide polymorphisms (SNPs) in MYOC and ABCA1 genes (rs12076134, rs183532, rs235875 and rs235913 in MYOC, rs2422493, rs2487042, rs2472496, rs2472493, rs2487032, rs2472459 and rs2472519 near ABCA1) using an improved multiplex ligation detection reaction (iMLDR) technique. The genetic association analyses were performed by PLINK using a logistic regression model. The association between genotypes and ocular biometric parameters was performed by SPSS using generalized estimation equation. Bonferroni corrections were implemented and the statistical power was calculated by the Power and Sample Size Calculation. RESULTS: Two SNPs rs183532 and rs235875 as well as a haplotype TTC in MYOC were nominally associated with PACG despite the significance was lost after Bonferroni correction. No association was observed between ABCA1 and PACG, neither did the association between these variants and ACD as well as AL. CONCLUSION: The present study suggests MYOC and ABCA1 do not play a part in the pathogenesis of PACG as well as the regulation of ocular biometric parameters in a northern Chinese population. Further investigations with large sample size are needed to verify this consequence.

High myopia (HM) is one of the leading causes of irreversible vision loss in the world. Many myopia loci have been uncovered with linkage analysis, genome-wide association studies, and sequencing analysis. Numerous pathogenic genes within these loci have been detected in a portion of HM cases. In the present study, we aimed to investigate the genetic basis of 103 patients with nonsyndromic HM, focusing on the reported causal genes.A total of 103 affected individuals with nonsyndromic HM were recruited, including 101 patients with unrelated sporadic HM and a mother and son pair. All participants underwent comprehensive ophthalmic examinations, and genomic DNA samples were extracted from the peripheral blood. Whole exome sequencing was performed on the mother and son pair as well as on the unaffected father. Sanger sequencing was used to identify mutations in the remaining 101 patients. Bioinformatics analysis was subsequently applied to verify the mutations.An extremely rare mutation inWe provide further evidence for the potential role of

Purpose: The aim of this study was to investigate the genetic basis and pathogenic mechanism of variable maculopathies, ranging from mild photoreceptor degeneration to central areolar choroidal dystrophy, in a five-generation family. Methods: Clinical characterizations, whole-exome sequencing, and genome-wide linkage analysis were carried out on the family. Zebrafish models were used to investigate the pathogenesis of GUCA1A mutations. Results: A novel mutation, GUCA1A p.R120L, was identified in the family and predicted to alter the tertiary structure of guanylyl cyclase-activating protein 1, a photoreceptor-expressed protein encoded by the GUCA1A gene. The mutation was shown in zebrafish to cause significant disruptions in photoreceptors and retinal pigment epithelium, together with atrophies of retinal vessels and choriocapillaris. Those phenotypes could not be fully rescued by exogenous wild-type GUCA1A, suggesting a likely gain-of-function mechanism for p.R120L. GUCA1A p.D100E, another mutation previously implicated in cone dystrophy, also impaired the retinal pigment epithelium and photoreceptors in zebrafish, but probably via a dominant negative effect. Conclusion: We conclude that GUCA1A mutations could cause significant variability in maculopathies, including central areolar choroidal dystrophy, which represents a severe pattern of maculopathy. The diverse pathogenic modes of GUCA1A mutations may explain the phenotypic diversities. Genet Med advance online publication 26 January 2017

Aim To describe the clinical characteristics with genetic lesions in a Chinese family with Crouzon syndrome. Methods All five patients from this family were included and received comprehensive ophthalmic and systemic examinations. Direct sequencing of the FGFR2 gene was employed for mutation identification. Crystal structure analysis was applied to analyze the structural changes associated with the substitution. Results All patients presented typical Crouzon features, including short stature, craniosynostosis, mandibular prognathism, shallow orbits with proptosis, and exotropia. Intrafamilial phenotypic diversities were observed. Atrophic optic nerves were exclusively detected in the proband and her son. Cranial magnetic resonance imaging (MRI) implied a cystic lesion in her sellar and third ventricular regions. A missense mutation, FGFR2 p.Cys342Trp, was found as disease causative. This substitution would generate conformational changes in the extracellular Ig-III domain of the FGFR-2 protein, thus altering its physical and biological properties. Conclusion We describe the clinical presentations and genotypic lesions in a Chinese family with Crouzon syndrome. The intrafamilial phenotypic varieties in this family suggest that other genetic modifiers may also play a role in the pathogenesis of Crouzon syndrome.

The reaction of Zn(OAc)2·2H2O and pyrazine-2,6-dicarboxylic acid (H2pzda) with 2,2′-bipyridine (2,2′-bpy), 1,10-phenanthroline (phen) or 1,2-bis(4-pyridyl)-ethane (bpe) gave rise to three new Zn(II) complexes: [Zn(pzda)(2,2′-bpy)(H2O)]·0.5H2O (1), {[Zn(pzda)(phen)(H2O)]·H2O}2 (2) and [Zn2(pzda)2(bpe)(H2O)4]·1.75H2O (3), respectively. For 1, it is a mononuclear structure which is assembled into 3D supramolecular architecture by strong hydrogen bonds (O–H⋯O, O–H⋯N) as well as π–π stacking interactions. In 2, there are two similar mononuclear units, which are further constructed by the hydrogen bonds and π–π stacking interactions into zipper-like supramolecular structure. However, for 3, the bpe ligand bridges two Zn(II) ions cooperated with blocking ligand pzda into binuclear unit, and then the binuclear molecules are alternatively assembled into 3D supramolecular network by hydrogen bonds between the coordinated water molecules and the carboxylate oxygen atoms. The thermal properties of complexes were also investigated.

Five new copper(II) complexes [Cu(dbsf)(H2O)]n · 0.5n(i-C3H7OH) (1), [Cu(dbsf)(4,4′-bpy)0.5]n · nH2O (2), [Cu(dbsf)(2,2′-bpy)(H2O)]2 · (n-C3H7OH) · 0.5H2O (3), [Cu(dbsf)(phen)(H2O)]2 · 1.5H2O (4) and [Cu(dbsf)(2,2′-bpy)(H2O)]n · n(i-C3H7OH) (5) (H2dbsf = 4,4′-dicarboxybiphenyl sulfone, 4,4′-bpy = 4,4′-bipyridine, 2,2′-bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, i-C3H7OH = isopropanol, n-C3H7OH = n-propanol) have been synthesized under hydro/solvothermal conditions. All of the complexes are assembled from V-shaped building blocks, [Cu(dbsf)]. Complex 1 is composed of 1D double-chains. In complex 2, dbsf2− ligands and 4,4′-bpy ligands connect Cu(II) ions into catenane-like 2D layers. These catenane-like 2D layers stack in an ABAB fashion to form a 3D supramolecular network. Complexes 3 and 4 are 0D dimers, in which two [Cu(dbsf)] units encircle to form dimetal macrocyclic molecules. However, in complex 5, the V-shaped building blocks [Cu(dbsf)] are joined head-to-tail, resulting in the formation of infinite tooth-like chains. The different structures of complexes 3 and 5 may be attributed to the different solvent molecules included.

Three novel zinc complexes [Zn(dbsf)(H2O)2] (1), [Zn(dbsf)(2,2′-bpy)(H2O)]·(i-C3H7OH) (2) and [Zn(dbsf)(DMF)] (3) (H2dbsf = 4,4′-dicarboxybiphenyl sulfone, 2,2′-bpy = 2,2′-bipyridine, i-C3H7OH = iso-propanol, DMF = N,N-dimethylformamide) were first obtained and characterized by single crystal X-ray crystallography. Although the results show that all the complexes 1–3 have one-dimensional chains formed via coordination bonds, unique three-dimensional supramolecular structures are formed due to different coordination modes and configuration of the dbsf2− ligand, hydrogen bonds and π–π interactions. Iso-propanol molecules are in open channels of 2 while larger empty channels are formed in 3. As compared with emission band of the free H2dbsf ligand, emission peaks of the complexes 1–3 are red-shifted, and they show blue emission, which originates from enlarging conjugation upon coordination. Copyright © 2006 John Wiley & Sons, Ltd.

The one-pot hydrothermal reaction of CuCl2 with H2CPOA and 4,4′-bpy results in two new coordination polymers, [Cu(CPOA)(4,4′-bpy)(H2O)2]·1.5H2O (1) and [Cu2(HCPOA)4(4,4′-bpy)4] (2) (H2CPOA4-carboxyphenoxy acetic acid, 4,4′-bpy4,4′-bipyridine) since CPOA2− anions reach equilibrium with HCPOA− anions in the reaction system. The crystal structure of 1 shows a triple interpenetration CdSO4-like net with 1D channel, in which lattice water molecules are located. Complex 2 is a ladder-like 1D double chain structure assembled through coordination bonds and O–H···N hydrogen bonds.

Three new lanthanide coordination polymers with 1,2,4,5-benzenetetracarboxylic acid, Pr2(betc)2(4,4′-bpyH2)·0.25H2O (1), Ln2(betc)2(4,4′-bpyH2) (Ln=Eu (2), Gd (3)) were hydrothermally prepared. The crystallographic data of 1–3 show that they are isostructural, and possess 3D framework with 1D rhomboid channels, where the 4,4′-bipyridine molecules exist steadily via hydrogen bonds. Meanwhile, a supramolecular structure of (4,4′-bpyH2)2(betc) (4) was also obtained by hydrothermal reaction. The results of 1–4 indicate that 4,4′-bipyridine molecule acting as a template plays an important role in the formation of complexes 1–3, and thus has a synergistic action in the construction of 3D framework with large channels.

First examples of lanthanide coordination polymers with 4,4′-biphenyldicarboxylic acid (4,4′-H 2 bpdc), Ln(4,4′-Hbpdc)(4,4′-bpdc)(H 2 O) 2 (Ln=Pr(1), Eu( 2 ), Gd( 3 )) and Er(4,4′-bpdc) 1.5 (H 2 O) 2 ( 4 ) were prepared by the solvothermal synthesis. Crystallographic data show that complexes 1 – 3 are isostructural and each lanthanide(III) ion is coordinated to six 4,4′-Hbpdc ligands, and display 3D sandwich structure with lanthanide ion layers and organic ligand layers alternately linking up with each other. Complex 4 shows different coordination modes of 4,4′-bpdc ligands from 1 – 3 and each Er(III) ion is attached to four 4,4′-bpdc ligands to construct 3D sandwich structure. The emission spectrum of 2 shows one Eu 3+ ion site, which is consistent with the results of the X-ray crystal structure analysis.

In the four new lanthanide coordination polymers {[La2(2,2′-dpdc)3(phen)(H2O)]·2H2O}n (1), [Eu2(2,2′-dpdc)3(phen)(H2O)2]n (2), {[Ln2(2,2′-dpdc)3(phen)2(H2O)2]·4H2O}n [Ln = Tb (3), Yb (4)] (2,2′-dpdc = 2,2′-diphenyldicarboxylate, phen = 1,10-phenanthroline), prepared by hydrothermal synthesis, the 2,2′-dpdc dianion affords tetradentate, pentadentate, and hexadentate coordination modes. Complex 1 is a two-dimensional network of infinite 1-D chains assembled through π−π interactions, with nine- and ten-coordinate La3+, and arranged in wave-like layers. In 2, Eu3+ possesses nine- and ten-coordinate geometries bridged by 2,2′-dpdc ligands to give a 3-D structure. The isomorphous complexes 3 and 4, in which Tb3+ and Yb3+ ions are both nine-coordinate, have two-dimensional structures of 1-D zigzag chains stacked via hydrogen bonds and π−π interactions of phen molecules. The high-resolution emission spectrum of 2 shows two Eu3+ ion sites, which is consistent with the results of the X-ray crystal structure analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

Lanthanide complexes with a one-dimensional chain, [Ln2(dpdc)3(H2O)2]n [Ln = La (1), Pr (2), Eu (3), Tb (4); dpdc = 2,2′-diphenyldicarboxylate] were obtained by hydrothermal reaction of lanthanide(III) chlorides and 2,2′-diphenyldicarboxylic acid, and characterized by X-ray diffraction. The crystal structure data reveal that they are isostructural. In the asymmetric unit, the two Ln3+ ions are both eight-coordinate but they have different coordination environments. Lanthanide ions arranged in a zigzag manner are bridged by the dpdc ligands into a 1-D chain, while the structure appears like a pinwheel viewed along the c axis. In these complexes, 2,2′-diphenyldicarboxylate anions exhibit tetradentate and pentadentate coordination modes. A laser-induced highresolution spectrum (resolution: 0.2 cm−1) of 3 was obtained, which shows two Eu3+ sites in 3. This is in agreement with the results of single-crystal X-ray diffraction studies of 3. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

To investigate whether the polymorphisms of insulin-like growth factor-1 (IGF-1) gene and its regulatory regions are associated with extreme high myopia.A case-control analysis of 302 subjects with extreme high myopia and 401 controls was undertaken. Genomic DNA was obtained from peripheral blood. Seven tag single nucleotide polymorphisms (tSNP) across the IGF-1 gene region were selected to capture the majority of genetic variation. All tSNP were genotyped using the MassArray platform and MALDI-TOF analysis. Genotypic distribution was tested for Hardy-Weinberg equilibrium. Statistical analyses were performed using the SPSS (version 13.0: SPSS Science, Chicago, IL) software. The genotype and allele frequencies were evaluated using the χ(2) tests and performed by Bonferroni corrections for multiple comparisons. The significance of the differences in the estimated haplotype frequencies between the myopia and control groups was examined on Haploview 4.2 using χ(2) tests, and haplotypes were corrected by using permutation test after running 50 000 times.Among seven different IGF-1 tSNP tested, the allele frequencies of four tSNP-rs5742629(A/G), rs12423791(G/C), rs35766 (G/A) and rs1457601(T/A) in the myopia and the control groups were A(56.5%, 62.3%)/G(43.5%, 27.7%), G(70.4%, 77.1%)/C(29.6%, 22.9%), G(33.9%, 28.8%)/A(66.1%, 71.2%), T(72.5%, 77.3%)/A(27.5%, 22.7%), respectively. And they showed significant differences (χ(2) = 4.968, 8.059, 4.250, 4.245, P0.05) between the two groups. However, only rs12423791 remained significance after Bonferroni correction. The haplotype GC of rs5742629-rs12423791 was associated with extreme high myopia (P = 0.033) after 50 000 permutations for multiple comparisons as well.The polymorphism of rs12423791 in IGF-1 may be associated with extreme high myopia in the Chinese population.

To screen the mutation in the RPGR gene in a large Chinese family with X-linked recessive retinitis pigmentosa (RP) and to describe the phenotype in affected males and female carriers.Ophthalmic examinations were performed in 77 family members of a RP pedigree to identify affected individuals. Polymerase chain reaction (PCR) and direct sequencing were used for screening of mutations in RPGR gene exon ORF15.Mutation screening demonstrated a novel mutation, g.ORF15 + 577_578delAG, which caused an open reading frameshift and resulted in premature truncation of the RPGR protein. This mutation was detected in 8 affected male individuals and 14 obligate female carriers in this family and was found to segregate with the phenotype in this family. This mutation led to a severe RP phenotype in male affected individuals with some variability in the age of onset of night blindness and loss of visual acuity, but was recessive in female carriers without a RP phenotype. However the most striking phenotypic feature in female carriers in this pedigree was moderate to high myopia with refractive error ranging from -5.00 D to -22.00 D in 14 female carriers.This novel mutation in RPGR ORF15 causes serious RP phenotype in males and no RP phenotype in female carriers. Moderate to high myopia was a particular feature for female carriers in this pedigree. Our finding expands the spectrum of RPGR mutations causing RP and phenotypic spectrum of the disease in Chinese family, which is useful for further genetic consultation and genetic diagnosis.

Nine new metal complexes with an asymmetric H2cpoa ligand, [Co(Hcpoa)2(bpe)2(H2O)2] (1), [Co(cpoa)(bpe)1.5(H2O)]·H2O (2), [Co(Hcpoa)2(4,4′-bpy)2] (3), [Co(4,4′-bpy)(H2O)4]·[Co(cpoa)2(H2O)2]·2H2O (4), [Ni(cpoa)(4,4′-bpy)(H2O)2] (5), [Ni(cpoa)(bpe)1.5(H2O)]·H2O (6), [Zn2(cpoa)2(bpe)(H2O)] (7), [Zn(cpoa)(bpe)0.5]·0.5(i-C3H7OH) (8) and [Zn(cpoa)(bpe)0.5]·0.5(n-C3H7OH) (9) (H2cpoa = 4-carboxyphenoxy acetic acid, bpe = 1,2-bis(4-pyridyl)ethane, 4,4′-bpy = 4,4′-bipyridine) were synthesized under hydro/solvothermal conditions. X-ray single-crystal structural analyses reveal that they have metal–organic frameworks ranging from 0D (1), 1D (3, 4), 2D (5, 7, 8) to 3D structure (2, 6, 9). The reaction of the CoCl2/H2cpoa/bpe (1 : 1 : 1) system results in the formation of complex 1 at the starting pH of ca. 8, and complex 2 at 12. The reaction of CoCl2/H2cpoa/4,4′-bpy (1 : 1 : 1) forms complex 3 with a 1D chain structure, while a molar ratio of 1 : 1 : 0.5 leads to the formation of complex 4 with two 1D metal–organic frameworks of rarely reported homometal complex ion pairs. By changing the added organic solvent, the 2D layer framework of complex 8 and the microporous 3D framework of complex 9 were obtained under the same reaction conditions. The guest n-C3H7OH molecules occupy 1D channels in 9. Thermogravimetric and powder X-ray diffraction analyses show that the microporous 3D framework of 9 is maintained after the removal of the guest molecule. And a reversible dealcoholization/realcoholization process can be observed. The magnetic measurements show antiferromagnetic interactions between the metal ions in 2, 4 and 5, and antiferromagnetic interaction in the range of 300–18 K and ferromagnetic interaction between Ni(II) ions below 18 K in 6.