Catalyst-Controlled Diastereodivergent Construction of Vicinal Sulfur-Functionalized Quaternary and Tertiary Stereocenters

A catalyst-controlled diastereodivergence is described for the enantioselective conjugate addition of <i>o</i>-hydroxyphenyl-substituted <i>p-</i>QMs with 5<i>H</i>-thiazol-4-ones. The reactions were enabled by two chiral complementary, nonenantiomeric catalysts to furnish a series of adducts possessing vicinal sulfur-functionalized quaternary and tertiary stereocenters in high yields with excellent asymmetric induction. Moreover, <i>o</i>-QMs generated in situ from <i>o</i>-hydroxybenzyl alcohols were also compatible

Identification of two recurrent mutations of COL1A1 gene in Chinese Van der Hoeve syndrome patients

<p><b>Conclusion</b>: The two discovered mutations in <i>COL1A1</i> gene, although first reported in China, are recurrent ones that have also been found elsewhere in type I osteogenesis imperfecta patients, suggesting their role in pathogenesis of Van der Hoeve syndrome. <b>Objectives</b>: The aim of this study is to find mutational patterns of <i>COL1A1</i> gene that may account for the putative Van der Hoeve syndrome in the patients carrying symptoms of osteogenesis imperfecta, blue sclera, and conductive deafness. <b>Method</b>: Genomic DNA was extracted from the blood of each patient and exons of <i>COL1A1</i> gene were amplified using PCR and sequenced. <b>Results</b>: Sequencing in some of the two family members revealed point mutations in exon 26 (c.1792C > T) and exon 43 (c.3076C > T) of <i>COL1A1</i> gene, respectively.</p

Genetic and Phenotypic Heterogeneity in Chinese Patients with Waardenburg Syndrome Type II

<div><p>Waardenburg Syndrome (WS) is an autosomal-dominant disorder characterized by sensorineural hearing loss and pigmentary abnormalities of the eyes, hair, and skin. Microphthalmia-associated transcription factor (<i>MITF</i>) gene mutations account for about 15% of WS type II (WS2) cases. To date, fewer than 40 different <i>MITF</i> gene mutations have been identified in human WS2 patients, and few of these were of Chinese descent. In this study, we report clinical findings and mutation identification in the <i>MITF</i> gene of 20 Chinese WS2 patients from 14 families. A high level of clinical variability was identified. Sensorineural hearing loss (17/20, 85.0%) and heterochromia iridum (20/20, 100.0%) were the most commonly observed clinical features in Chinese WS2 patients. Five affected individuals (5/20, 25.0%) had numerous brown freckles on the face, trunk, and limb extremities. Mutation screening of the <i>MITF</i> gene identified five mutations: c.20A>G, c.332C>T, c.647_649delGAA, c.649A>G, and c.763C>T. The total mutational frequency of the <i>MITF</i> gene was 21.4% (3/14), which is significantly higher than the 15.0% observed in the fair-skinned WS2 population. Our results indicate that <i>MITF</i> mutations are relatively common among Chinese WS2 patients.</p></div

Pedigrees of the Chinese WS2 families WS01, WS02, and WS03, and audiograms of some affected male and female subjects.

<p>High clinical variability was observed even within the same family. Not all affected persons manifested all clinical features. Circle, female; square, male; filled quadrants indicate phenotype associated with WS, upper left, premature graying hair; lower left, freckles on the skin; upper right, hearing loss; lower right, heterochromia iridis; arrow, the proband; *, DNA samples available.</p

Summary of Clinical Data for 20 Chinese WS2 Patients.

<p>A, complete heterochromia iridis; B, partial or segmental heterochromia iridis; C, brilliant blue iris; Skin, numerous brown freckles on the face, trunk, and limb extremities; W, W index; HL, hearing loss; +, sign present; −, sign absent.</p

Mutation analyses of Chinese WS2 families WS01, WS02, WS04, WS08, and WS09.

<p>A. DNA sequence chromatograms showing heterozygous missense c.20A>G mutation identified in family WS02, compared with wild-type controls. The structure of MITF indicates the position of c.20A>G mutation in exon 1 and p. Y7C outside the HLH domain. B. DNA sequence chromatograms showing heterozygous missense c.332C>T mutation identified in family WS09, compared with wild-type controls. The structure of MITF indicates the position of c.332C>T mutation in exon 3 and p. A111V outside the HLH domain. C. DNA sequence chromatograms showing heterozygous c.647_649delGAA deletion mutation identified in family WS04, compared with wild-type controls. The structure of MITF indicates the position of c.647_649delGAA mutation in exon 7 and p. R217del in the HLH domain. D. DNA sequence chromatograms showing heterozygous missense c.649A>G mutation identified in family WS08, compared with wild-type controls. The structure of MITF indicates the position of c.649A>G mutation in exon 7 and p. R217G in the HLH domain. E. DNA sequence chromatograms showing heterozygous nonsense c.763C>T mutation identified in family WS01, compared with wild-type controls. The structure of MITF indicates the position of c.763C>T mutation in exon 8 and p. R255X in the HLH domain. F. Conservation analysis shows that the Arg residue at 217 in MITF is conserved across human, Pan troglodytes, macaca, canis, bos, Mus musculus, Rattus norvegicus, gallus, and Danio rerio. G. Schematic illustration of <i>MITF</i> gene structure showing the position of the mutations. AD1-3, transactivation domains; b, basic domain; HLH, helix-loop-helix domain; LZ, leucine zipper domain.</p

Summary of <i>MITF</i> Gene Mutations Identified in Chinese WS2 Patients.

<p>a. Description of the mutations is based on the GenBank reference sequence for the <i>M</i> isoform of the <i>MITF</i> gene: NM_000248.3.</p><p>b. Amino acid numbering is based on GenBank Reference Sequence: NP_000239.1.</p>*<p>, mutations first described in a Chinese population.</p><p>The English in this document has been checked by at least two professional editors, both native speakers of English. For a certificate, please see: <a href="http://www.textcheck.com/certificate/O0uNHd" target="_blank">http://www.textcheck.com/certificate/O0uNHd</a>.</p

Pedigree of three-generation Chinese family GD-O031 with prelingual progressive hearing impairment and audiograms of 11 affected subjects.

<p>Affected subjects are denoted in black. Based on the audiograms of the affected subjects (red, right ear; black, left ear), the severity of hearing impairment was moderate to severe and progress slowly with increasing patient age. The hearing loss involved all frequencies.</p

Identification of a Novel <i>TECTA</i> Mutation in a Chinese DFNA8/12 Family with Prelingual Progressive Sensorineural Hearing Impairment

<div><p>Tectorial membrane, an extracellular matrix of the cochlea, plays a crucial role in the transmission of sound to the sensory hair cells. Alpha-tectorin is the most important noncollagenous component of the tectorial membrane and the otolith membrane in the maculae of the vestibular system. Defects in <i>TECTA</i>, the gene encodes alpha-tectorin, are cause of both dominant (DFNA8/12) and recessive (DFNB21) forms of deafness. Here, we report a three-generation Chinese family characterized by prelingual progressive sensorineural hearing impairment. We mapped the disease locus to chromosome 11q23-24 region, overlapping with the DFNA8/12 locus. Sequencing of candidate gene <i>TECTA</i> revealed a heterozygous c.5945C>A substitution in exon 19, causing amino acid substitution of Ala to Asp at a conservative position 1982. The A1982D substitution is consistent with hearing loss in this Chinese family and has not been found in 200 random control chromosomes. To our knowledge, this is the first <i>TECTA</i> mutation identified in Chinese population. Our data provides additional molecular and clinical information for establishing a better genotype–phenotype understanding of DFNA8/12.</p></div

Ultrasound image of the normal and abnormal fetuses.

<p>A: The ultrasound image of PGD fetus at the 12 weeks’ gestation showing intact skull and did not have an enlarged abdomen. B: The ultrasound image of the third pregnancy of this couple at the 14 weeks’ gestation showing occipital encephalocele and enlarged abdomen.</p