Mutation in The Nuclear‐Encoded Mitochondrial Isoleucyl–tRNA Synthetase IARS2 in Patients with Cataracts,Growth Hormone Deficiency with Short Stature,Partial Sensorineural Deafness,and Peripheral Neuropathy or with Leigh Syndrome

Mutations in the nuclear‐encoded mitochondrial aminoacyl–tRNA synthetases are associated with a range of clinical phenotypes. Here, we report a novel disorder in three adult patients with a phenotype including cataracts, short‐stature secondary to growth hormone deficiency, sensorineural hearing deficit, peripheral sensory neuropathy, and skeletal dysplasia. Using SNP genotyping and whole‐exome sequencing, we identified a single likely causal variant, a missense mutation in a conserved residue of the nuclear gene IARS2, encoding mitochondrial isoleucyl–tRNA synthetase. The mutation is homozygous in the affected patients, heterozygous in carriers, and absent in control chromosomes. IARS2 protein level was reduced in skin cells cultured from one of the patients, consistent with a pathogenic effect of the mutation. Compound heterozygous mutations in IARS2 were independently identified in a previously unreported patient with a more severe mitochondrial phenotype diagnosed as Leigh syndrome. This is the first report of clinical findings associated with IARS2 mutations.     

A Homozygous Mutation in LYRM7/MZM1L Associated with Early Onset Encephalopathy,Lactic Acidosis,and Severe Reduction of Mitochondrial Complex III Activity

Mutations in nuclear genes associated with defective complex III (cIII) of the mitochondrial respiratory chain are rare, having been found in only two cIII assembly factors and, as private changes in single families, three cIII structural subunits. Recently, human LYRM7/MZM1L, the ortholog of yeast MZM1, has been identified as a new assembly factor for cIII. In a baby patient with early onset, severe encephalopathy, lactic acidosis and profound, isolated cIII deficiency in skeletal muscle, we identified a disease‐segregating homozygous mutation (c.73G>A) in LYRM7/MZM1L, predicting a drastic change in a highly conserved amino‐acid residue (p.Asp25Asn). In a mzm1Δ yeast strain, the expression of a mzm1^D25N mutant allele caused temperature‐sensitive respiratory growth defect, decreased oxygen consumption, impaired maturation/stabilization of the Rieske Fe–S protein, and reduced complex III activity and amount. LYRM7/MZM1L is a novel disease gene, causing cIII‐defective, early onset, severe mitochondrial encephalopathy.     

DGAT2 Mutation in a Family with Autosomal‐Dominant Early‐Onset Axonal Charcot‐Marie‐Tooth Disease

Charcot‐Marie‐Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal‐dominant axonal CMT with early‐onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O‐acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum‐mitochondrial‐associated membrane protein, acyl‐CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal‐dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.     

Two Siblings with Homozygous Pathogenic Splice‐Site Variant in Mitochondrial Asparaginyl–tRNA Synthetase (NARS2)

A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl–tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In‐gel activity staining after blue native‐polyacrylamide gel electrophoresis confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole‐exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3′ splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV‐transformed lymphoblasts, a specific decrease in the amount of charged mt‐tRNA^Asn was demonstrated as compared with controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease‐associated aaRS2.     

Two unrelated pedigrees with achondrogenesis type 1b carrying a Japan‐specific pathogenic variant in SLC26A2

We present two unrelated Japanese pedigrees with achondrogenesis type 1b (ACG1B), characterized by prenatally lethal fetal hydrops and severe micromelia. The affected members in these pedigrees carried a common homozygous missense point mutation in solute carrier family 26 member 2 (SLC26A2), a gene associated with ACG1B (NM_000112:c.1987G>A). This loss‐of‐function point mutation causes substitution of glycine 663 with arginine in a highly conserved loop domain of SLC26A2. Interestingly, only a few cases of this mutation have been registered in Japanese genomic databases, and there are no reports of this mutation in any major genomic databases outside Japan. Furthermore, we confirmed the presence of a homozygous stretch of approximately 75 kb surrounding the pathogenic variant. Our findings suggest that this missense point mutation in SLC26A2, which is likely the cause of the ACG1B phenotypes in these unrelated fetuses, is distributed exclusively in Japan.     

Iridium(III) Complexes with PEO and PS Polymer Macroligands and Light‐Emitting Properties: Synthesis and Characterization

Summary: On the basis of terpyridine functionalized poly(ethylene oxide) (PEO) and poly(styrene) (PS), a series of light‐emitting iridium(III) compounds was effectively synthesized. The respective iridium(III) target compounds were prepared by grafting chloro‐bridged precursor complexes [Ir(ppy)₂‐μ‐Cl]₂ (ppy = phenylpyridine) and [Ir(ppy‐CHO)₂‐μ‐Cl]₂ (ppy‐CHO = 4‐(2‐pyridyl)benzaldehyde) onto terpyridine functionalized PEO and PS tails. 1D and 2D NMR characterization was performed revealing the expected resonances. Gel permeation chromatography (GPC) proved the stability and purity of the targeted materials. Preliminary investigations of the light‐emitting properties were carried out by standard methods such as UV‐vis and steady‐state luminescence spectroscopy. The morphology and the quality of films of these iridium(III) compounds were furthermore investigated using AFM. Improved stability on the electrode surface was illustrated using cyclic voltammetry. One of the polymer materials was compared to the neat complex, which showed quick degradation.

Green and orange light‐emitting iridium(III) complexes with two cyclometalating ligands and one terpyridine ligand with PS tails.     

Distinct craniofacial‐skeletal‐dermatological dysplasia in a patient with W290C mutation in FGFR2

Mutations in the fibroblast growth factor receptor genes (FGFR) have been known to be associated with many craniosynostosis syndromes with overlapping phenotypes. We studied a 15‐year‐old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies of T9–12, humero‐radio‐ulnar joints, intercarpal joints, distal interphalangeal joints of fifth fingers, fibulo‐tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was a heterozygous for a 870G → T change resulting in a W290C amino acid substitution in the extracellular domain of the fibroblast growth factor receptor 2 gene (FGFR2). This mutation has previously been reported in a patient with severe Pfeiffer syndrome type 2 that is distinct from the craniosynostosis in our patient. These findings emphasize locus, allelic, and phenotypic heterogeneity of craniofacial‐skeletal‐dermatological syndrome due to FGFR2 mutations. © 2002 Wiley‐Liss, Inc.     

Ultrahigh‐Molecular‐Weight Polyethylene by Using a Titanium Calix[4]arene Complex with High Thermal Stability under Polymerization Conditions

The new complex 25,27‐dipropyloxy‐26,28‐dioxocalix[4]arene titanium (IV) dichloride ( 1 ) was evaluated as an ethylene polymerization catalyst. Activation with methylalumoxane resulted in an active system producing ultrahigh‐molecular‐weight polyethylene. As expected for a Ziegler‐Natta catalyst, the polymerization reaction follows first‐order kinetics. The most striking feature of the catalytic system ( 1 /MAO) is its remarkably high thermal stability. This peculiarity probably relies on the electronic stabilization of the metal center by the two coordinating propoxy groups.

     

Temperature and pH Dual‐Responsive Behavior of Dendritic Poly(N‐isopropylacrylamide) with a Polyoligomeric Silsesquioxane Core and Poly(2‐hydroxyethyl methacrylate) Shell

Novel temperature and pH dual‐responsive dendritic polyoligomeric silsesquioxane (POSS)–poly(N‐isopropylacrylamide) (PNIPAm)–poly(2‐hydroxyethyl methacrylate) (PHEMA) copolymers are prepared via atom transfer radical polymerization and click reactions. The cloud points (T_c) decrease with decreasing pH from 10.0 to 5.0 due to the weakened inter‐molecular interactions and enhanced intra‐molecular hydrogen bonding, whereas the T_c exhibits a small increase from pH 5.0 to 4.0 because of the better solvation of PHEMA at highly acidic conditions. The above findings are corroborated by the different sizes of aggregates observed by dynamic light scattering. The encapsulation of a fluorescent dye and stimulated release by temperature and pH changes are also demonstrated.     

Lung hypoplasia in a patient with del(2)(q33‐q35) demonstrated by chromosome microdissection

We report on a 17‐month‐old girl with multiple malformations, including lung hypoplasia, multiple ventricular septal defects, craniofacial anomalies, and malrotation of the intestine. Moreover, the patient showed Robin sequence, developmental delay, as well as pre‐ and postnatal growth retardation. Postnatal cytogenetic analysis revealed an interstitial deletion on the long arm of chromosome 2. Microdissection and reverse chromosome painting of the aberrant chromosome 2 as well as FISH with a panel of chromosome 2q band‐specific YACs mapped the deletion to 2q33‐q35. Lung hypoplasia has not been described so far in patients with del(2)(q33‐q35). A review of previously reported patients showed variable phenotypes apparently due to different deleted chromosomal segments. Am. J. Med. Genet. 94:184–188, 2000. © 2000 Wiley‐Liss, Inc.     

Triggering the Thermosensitive Properties of Hydrophobically Modified Poly(N‐isopropylacrylamide) by Complexation with Cyclodextrin Polymers

Summary: Hydrophobically modified poly(N‐isopropylacrylamide) (PNIPAM) containing either an adamantyl or a dodecyl group were prepared and characterized. Self‐association in aqueous solutions was evidenced by fluorescence measurements using pyrene as a probe. The lower critical solution temperatures (LCST) were determined from cloud point measurements. They strongly depended on the hydrophobic group and the substitution level. The association between hydrophobically modified PNIPAM and β‐cyclodextrin (monomers and polymers) was investigated by cloud point and viscosity measurements. The presence of β‐cyclodextrin monomers generally shifted the LCST to a higher temperature, the complexation increasing the solubility of PNIPAM chains. β‐Cyclodextrin polymers mixed with hydrophobically modified PNIPAM generated supramolecular assemblies. This was evidenced by viscosity measurements of the mixtures at temperatures lower than the LCST. Moreover, depending on the substitution level of the PNIPAM, the LCST was increased (1% hydrophobic groups) or decreased (4% hydrophobic groups) by more than 10 °C upon β‐cyclodextrin polymer addition.

Transmission variations of different mixtures of PNIPAM‐C12 with cyclodextrin compounds vs temperature.     

Duplication of (2)(q11.1‐q13.2) in a boy with mental retardation and cleft lip and palate: Another clefting gene locus on proximal 2q?

A 4‐year‐old boy with left cleft lip and cleft palate, multiple minor anomalies and developmental delay revealed an abnormal chromosome 2 with enlarged proximal long arm, de novo, in his karyotype. Fluorescence in situ hybridization with a chromosome 2 library and band‐specific YACs confined the duplicated segment to 2q11.1‐q13.2 and indicated a direct tandem duplication due to unbalanced crossover between chromatids. © 2002 Wiley‐Liss, Inc.