A novel mutation in CRYBB1 associated with congenital cataract-microcornea syndrome: the p.Ser129Arg mutation destabilizes the βB1/βA3-crystallin heteromer but not the βB1-crystallin homomer

Congenital cataract-microcornea syndrome (CCMC) is a clinically and genetically heterogeneous condition characterized by lens opacities and microcornea. It appears as a distinct phenotype of heritable congenital cataract. Here we report a large Chinese family with autosomal dominant congenital cataract and microcornea. Evidence for linkage was detected at marker D22S1167 (LOD score [Z]=4.49, recombination fraction [θ]=0.0), which closely flanks the a-crystallin gene cluster locus. Direct sequencing of the candidate aB1-crystallin gene (CRYBB1) revealed a c.387C>A transversion in exon 4, which cosegregated with the disease in the family and resulted in the substitution of serine by arginine at codon 129 (p.Ser129Arg). A comparison of the biophysical properties of the recombinant β-crystallins revealed that the mutation impaired the structures of both βB1-crystallin homomer and βB1/βA3-crystallin heteromer. More importantly, the mutation significantly decreased the thermal stability of βB1/βA3-crystallin but not βB1-crystallin. These findings highlight the importance of protein-protein interactions among β-crystallins in maintaining lens transparency, and provide a novel insight into the molecular mechanism underlying the pathogenesis of human CCMC.     

Contribution of syntaxin 1A to the genetic susceptibility to migraine: A case–control association study in the Spanish population

Migraine is a common neurological disorder with a complex inheritance pattern. Mutations in genes encoding proteins that are involved in ion transport across the neuronal membrane have been linked to rare monogenic variants of migraine. These or other related genes and proteins are also candidates to be involved in the inherited predisposition to the more common forms of migraine without aura (MO) or migraine with aura (MA). One of these proteins, syntaxin 1A, encoded by the STX1A gene, is a key molecule in ion channel regulation and synaptic exocytosis. We assessed the contribution of STX1A to migraine by analyzing three SNPs that cover the entire gene (rs6951030–rs941298–rs4363087), in a case–control association study in 210 migraine patients (102 MO, 86 MA, 22 hemiplegic migraine) and 210 sex-matched unrelated controls. The single-marker analysis revealed significant differences in both allele frequencies (P = 0.0087, OR = 1.48) and genotype distributions (P = 0.0133) of the rs941298 SNP between migraineurs and controls, with an overrepresentation of T-allele carriers in the migraine sample (OR = 1.78). We subsequently performed a haplotype-based analysis and observed evidence of an overrepresentation of the A–T–G (rs6951030–rs941298–rs4363087) allelic combination in migraine patients and an increased frequency of carriers of this risk haplotype (P = 0.008, OR = 1.71). These differences remained significant when patients were subdivided into MO and MA. When the control series was enlarged for rs941298, we confirmed the association only with the whole migraine group.     

A EPC Approach to the Residual Water in Erythrocytes

A novel approach has been developed to determine the amount of residual water in human erythrocyte at room temperature by electronic particle counter. Nacl solutions of 13 osmolalities were prepared and the equilibrium cell volumes in which were measured one by one. The isotonic volume, Vo, was obtained under the isotonic condition. The mean RBC volumes of 5 donors at each osmolality were fitted according to Boyle van‘t Hoff relationship, and the osmotically inactive volume, Vb, of erythrocyte was then determined. The results show that Vb＝50% Vo. More importantly, the final cell volume with regard to the solution of the highest concentration found to be kept at about 0. 5 V0. The difference between these two volumes is unconspicuous. According to the published data that non-water volume of human erythrocyte is about 28.3% of its isotonic volume, residual water of human erythrocyte can be gained by subtracting Vdry from Vf, that is Vrw----21.7% Vo Then it was concluded that the residual water of human lays in 2 states, one is bound water, and the other is free water.     

De novo 617G–A nucleotide mutation in the ACVR1 gene in a Taiwanese patient with fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disease with autosomal dominant transmission characterized by the presence of malformations of the big toes and of postnatal progressive heterotopic endochondral osteogenesis. We report the case of 3-year-old girl with dysplasia of the first metatarsal bones and progressive heterotopic ossificans of the right thigh due to previous diphtheria–tetanus–pertussis immunizations and several inappropriate surgical interventions. Direct sequence analysis identified a 617G–A nucleotide mutation in the patient but not in her parents or brother. Pedigree analysis suggests that a de novo mutation in the ACVR1 gene is responsible for the disease in this family. This is the first report of the results of a mutation analysis in a sporadic case of FOP in a Taiwanese patient.     

A mutation in the type Ⅱ hair keratin KRT86 gene in a Han family with monilethrix

Monilethrix, a congenital disease of hair, is usually associated with mutations in keratin genes, like KRT81, KRT83 and KRT86. We conducted this study to investigate the mutation of type Ⅱ human basic hair keratin hHb/ KRT gene in a Han family with monilethrix and obtain information for potential pathogenic mechanism study of monilethrix. Peripheral blood samples were drawn for genomic DNA detection. Exon 1 and exon 7 of the KRT81, KRT83 and KRT86 genes were amplified by PCR. All PCR products were sequenced directly using an ABI 310 DNA sequencer. These sequences were aligned with the standard sequences in GenBank using the BLAST software. PCR products were digested with restriction endonuclease and restriction fragment length polymorphism (RFLP) analysis was performed. In this study, we identified one novel mutation, which is a heterozygous transitional mutation of G→A at position 1,289 in exon 7 of the KRT86 gene [R430Q (KRT86)]. RFLP assays for the novel mutation excluded the possibility of polymorphism. The R430Q mutation of the KRT86 gene may be pathogenic for monilethrix. Meanwhile, we did not find any novel mutation or recurrent mutation in exons 1 and 7 of KRT81 and KRT83 and exon 1 of KRT86. There is a potential pathogenic gene in the subjects and our results expand the spectrum of mutations in the hHb6 gene.     

A point mutation in the 5′-untranslated leader that affects translational activation of the mitochondrial COX 3 mRNA

The 613-base 5-untranslated leader (5-UTL) of the Saccharomyces cerevisiae mitochondrial COX 3 mRNA contains the target of an mRNA-specific translational activator complex composed of at least three nuclearly encoded proteins. We have genetically mapped a collection of cox 3 point mutations, using a set of defined COX 3 deletions, and found one to be located in the region coding the 5-UTL. The strain carrying this allele was specifically defective in translation of the COX 3 mRNA. Nucleotide-sequence analysis showed that the allele was in fact a double mutation comprised of a single-base insertion in the 5-UTL (T inserted between bases-428 and-427 with respect to the start of translation) and a G to A substitution at+3 that changed the ATG initiation codon to ATA. Both mutations were required to block translation completely. The effects of the ATG to ATA mutation alone (cox 3-1) had previously been analyzed in this laboratory: it reduces, but does not eliminate, translation, causing a slow respiratory growth phenotype. The T insertion in the 5-UTL had no detectable respiratory growth phenotype as a single mutation. However, the 5-UTL insertion mutation enhanced the respiratory defective phenotype of missense mutations in pet 54, one of the COX 3-specific translational-activator genes. This phenotypic enhancement suggests that the-400 region of the 5-UTL, where the mutation is located, is important for Pet54p-COX 3 mRNA interaction.     

A novel intermediate mucolipidosis II/IIIαβ caused by GNPTAB mutation in the cytosolic N-terminal domain

Mucolipidosis (ML) II and ML IIIα/β are allelic autosomal recessive metabolic disorders due to mutations in GNPTAB. The gene encodes the enzyme UDP-GlcNAc-1-phosphotransferase (GNPT), which is critical to proper trafficking of lysosomal acid hydrolases. The ML phenotypic spectrum is dichotomous. Criteria set for defining ML II and ML IIIα/β are inclusive for all but the few patients with phenotypes that span the archetypes. Clinical and biochemical findings of the ‘intermediate'' ML in eight patients with the c.10A>C missense mutation in GNPTAB are presented to define this intermediate ML and provide a broader insight into ML pathogenesis. Extensive clinical information, including radiographic examinations at various ages, was obtained from a detailed study of all patients. GNPTAB was sequenced in probands and parents. GNPT activity was measured and cathepsin D sorting assays were performed in fibroblasts. Intermediate ML patients who share the c.10A>C/p.K4Q mutation in GNPTAB demonstrate a distinct, consistent phenotype similar to ML II in physical and radiographic features and to ML IIIα/β in psychomotor development and life expectancy. GNPT activity is reduced to 7–12% but the majority of newly synthesized cathepsin D remains intracellular. The GNPTAB c.10A>C/p.K4Q missense allele results in an intermediate ML II/III with distinct clinical and biochemical characteristics. This delineation strengthens the utility of the discontinuous genotype–phenotype correlation in ML II and ML IIIα/β and prompts additional studies on the tissue-specific pathogenesis in GNPT-deficient ML.     

A novel mutation impairing the tertiary structure and stability of γC-crystallin (CRYGC) leads to cataract formation in humans and zebrafish lens

Congenital cataract is one of the leading causes of human blindness. In this study, we identified a novel, heterozygous c.385G相似文献   

Did the GJB2 35delG mutation originate in Iran?

Mutations in GJB2 are a major cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in many populations. A single mutation of this gene (35delG) accounts for approximately 70% of GJB2 mutations that are associated with ARNSHL in Caucasians in many European countries and also in Iranian. In this study, we used PCR and restriction digestion to genotype five single nucleotide polymorphisms (SNPs) that define the genetic background of the 35delG mutation over an interval of 98 Kbp that includes the coding and flanking regions of GJB2. Two microsatellite markers, D13S175 and D13S141, were also analyzed in patients and controls. These data suggest that the 35delG mutation originated in northern Iran.     

A novel mutation of Twinkle in Perrault syndrome: A not rare diagnosis?

Perrault syndrome is a rare disorder characterized by ovarian dysgenesis, bilateral sensorineural hearing loss and associated with mutations in six mitochondrial proteins. Additional neurological features were also described. Herein, we report on a 27-year-old woman with Perrault syndrome (PS), moderate ataxia and axonal sensory-motor peripheral neuropathy in whom we identified compound heterozygous mutations in the TWNK gene (p.Val507Ile and the novel p.Phe248Ser variant). Fewer than 30 patients with PS have been reported worldwide. Neurological involvement is more frequently associated with mutations in TWNK and indicates possible genotype–phenotype correlations. TWNK mutations should be searched in patients with sensory ataxia, early onset bilateral sensorineural hearing loss, and ovarian dysfunction in women.     

Can the gracilis be used to replace the anterior cruciate ligament in the knee? A cadaver study

PurposeThe purpose of this study was to evaluate whether a four-strand gracilis-only graft can be used in anterior cruciate ligament (ACL) reconstruction.Study designCadaver study.MethodsThis study involved 16 cadaver knees. The length and diameter of the native ACL were measured in each one. The same measurements were performed on a four-strand graft of the gracilis only, the semitendinosus only and both tendons. Student's t-test was used to compare the various conditions.ResultsThe average diameter of the G4 construct was 0.07 mm greater (1%) than the native ACL (p = 0.044). The average cross-sectional area of the G4 construct was 1.2 mm² greater (3.9%) than the native ACL (p = 0.049). The G4 was on average 38.9 mm longer than the intra-articular portion of the ACL (p < 0.001).ConclusionA four-strand gracilis construct meets the anatomical specifications for use as an ACL reconstruction graft. By using the gracilis only, the morbidity associated with harvesting the gracilis and semitendinosus tendons should be reduced. Further studies must be performed to compare the biomechanical properties of this graft with other graft types and also to evaluate how this four-strand gracilis graft behaves in a clinical setting.     

Influenza A (H1N1) 2009 pandemic: was there a difference in the two waves in patients requiring admission to the intensive-care unit?

Influenza virus is prone to mutations that may alter the intensity of subsequent waves of infection. In this study, we evaluated whether outcomes were different in the two waves of the influenza A (H1N1) 2009 pandemic in patients admitted to the intensive-care unit. Age, gender, lag-time to presentation and APACHE-II scores were similar in both waves. Although ventilatory requirements were similar (36/37 vs. 36/39), non-significant reductions in the durations (days) of ventilation (10.3 ± 8.0 vs. 7.8 ± 9.4, p 0.11) and hospitalization (14.9 ± 10.5 vs. 12.3 ± 14.1, p 0.20) were observed in the second wave. The clinical profile and outcomes were not significantly different between the two waves among severely ill patients.     

A novel mutation, Ala315Ser, in FGFR2: a gene-environment interaction leading to craniosynostosis?

Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G --> T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.