Mutations in LOXHD1 gene can cause auditory neuropathy spectrum disorder.

Objectives: The aim of this paper was to study the auditory phenotype of three related children with sensorineural hearing loss (2 sisters and their cousin) following genetic analysis revealing mutations in LOXHD1. Methods: Genetic testing was conducted on three related children. They were assessed with a standard clinical test battery including distortion otoacoustic emissions, auditory brainstem responses and audiometry. Results: We identified heterozygous variants in LOXHD1 in a family of Irish/German and Italian/Irish ancestry with autosomal recessive auditory neuropathy spectrum disorder (ANSD). Mutations in LOXHD1 (MIM #613072) have been linked to an autosomal recessive nonsyndromic hearing loss (DFNB77), mapped to the locus 18q12-q21. All three subjects had evidence of some, albeit few, functioning cochlear hair cells as revealed by the presence of a cochlear microphonic and/or partial otoacoustic emissions early in life. Conclusion: To our knowledge, this is the first association between LOXHD1 mutations and ANSD in two patients who have been successfully managed with cochlear implants.

Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels.

Upon activation, the epidermal growth factor (EGF) receptor becomes phosphorylated and triggers a vast signaling network that has profound effects on cell growth. The EGF receptor is observed to assemble into clusters after ligand binding and tyrosine kinase autophosphorylation, but the role of these assemblies in the receptor signaling pathway remains unclear. To address this question, we measured the phosphorylation of EGFR when the EGF ligand was anchored onto laterally mobile and immobile surfaces. We found that cells generated clusters of ligand-receptor complex on mobile EGF surfaces, and displayed a lower ratio of phosphorylated EGFR to EGF when compared to immobilized EGF that is unable to cluster. This result was verified by tuning the lateral assembly of ligand-receptor complexes on the surface of living cells using patterned supported lipid bilayers. Nanoscale metal lines fabricated into the supported membrane constrained lipid diffusion and EGF receptor assembly into micron and sub-micron scale corrals. Single cell analysis indicated that clustering impacts EGF receptor activation, and larger clusters (>1 µm(2)) of ligand-receptor complex generated lower EGF receptor phosphorylation per ligand than smaller assemblies (<1 µm(2)) in HCC1143 cells that were engaged to ligand-functionalized surfaces. We investigated the mechanism of EGFR clustering by treating cells with compounds that disrupt the cytoskeleton (Latrunculin B), clathrin-mediated endocytosis (Pitstop2), and inhibit EGFR activation (Gefitinib). These results help elucidate the nature of large-scale EGFR clustering, thus underscoring the general significance of receptor spatial organization in tuning biochemical function.

High resolution linkage and linkage disequilibrium analyses of chromosome 1p36 SNPs identify new positional candidate genes for low bone mineral density.

UNLABELLED: A quantitative trait locus (QTL) for BMD maps to chromosome 1p36. We have analyzed a high density SNP panel from this region for linkage and association to BMD in 39 osteoporosis pedigrees. Our results support the presence of genes controlling BMD on 1p36 and indicate new candidates for further analyses. INTRODUCTION: Low BMD is one of the major risk factors for osteoporosis. Following a genome scan in a sample of Caucasian families recruited through probands with low BMD, a region on 1p36 near marker D1S214 received support as a QTL for BMD from linkage (maximum lod-score = 2.87) and linkage disequilibrium (LD) analysis (p < 0.01). METHODS: To better characterize the genetic risk factors for low BMD located in this genomic region, we have genotyped the same group of families for 1095 SNPs located across 11 Mb on 1p36. Linkage and LD analyses have been performed using the variance component approach. RESULTS: Multivariate linkage analysis indicated two QTLs for femoral neck BMD, lumbar spine BMD and trochanter BMD simultaneously on 1p36, with maximum lod-scores of 4.37 at 12 cM and 3.59 at 22 cM. LD analysis identified several SNPs potentially associated with BMD, including the RERE gene SNP rs11121179 (p = 0.000005 for lumbar spine BMD). Other candidate genes include G1P2, SSU72 and CCDC27 (each containing 1 SNP with p < 0.001 for at least one BMD trait). CONCLUSIONS: This study supports the presence in 1p36 of QTLs affecting BMD at multiple skeletal sites. Replication of our results in other independent cohorts is warranted.

A new polymorphism in the proteolipid protein (PLP1) gene and its use for carrier detection of PLP1 gene duplication in Pelizaeus-Merzbacher disease.

Pelizaeus Merzbacher Disease (PMD) is an X-linked recessive dysmyelinating disorder of the central nervous system. Most patients have point mutations in exons of the proteolipid protein (PLP1) gene or duplication of a genomic region that includes the PLP1 gene. We identified a common MspI polymorphism in intron 1 of the PLP1 gene and used it to determine carrier status for PLP1 gene duplication in PMD by using a quantitative PCR approach.

PCR identification of class I major histocompatibility complex genes transcribed in mouse blastocyst and placenta.

We used an RT-PCR based strategy to amplify, clone and sequence MHC class I genes transcribed in the blastocyst and placenta of BALB/c mice. The PCR primers used were capable of amplifying many novel class I sequences from genomic DNA. By comparing the resulting sequence data with known class I sequences, we identified a number of different class I genes transcribed in these tissues. These include H2-K, -D, -L and a novel sequence in blastocysts, and H2-K, -D, -L, -D2, -T9, -T13, -T17, -T18, -M2 and three additional novel sequences in placenta. We postulate that some members of this spectrum of blastocyst and placentally-expressed MHC class Ib genes may act together at the maternal-fetal interface in ways that are important for a successful pregnancy.

A new major histocompatibility complex class I b gene expressed in the mouse blastocyst and placenta.

Because of the role major histocompatibility complex (MHC) class I b molecules may play during mouse embryonic development, we thought it would be interesting to search for additional MHC class I b molecules that might be expressed in preimplantation embryos, and in particular in the trophoblastic lineage. We therefore screened a mouse preimplantation blastocyst cDNA library for MHC class I sequences. This search led to the identification and characterization of a new MHC class I b gene, blastocyst MHC. Sequences identical to the exons and 3' untranslated region of this gene have been found in many laboratory mouse strains, as well as in the related mouse species Mus spreciligus. The presence of this gene in mouse strains of different MHC class I haplotypes argues that blastocyst MHC is a unique, newly-described gene rather than a new allele of a previously described mouse MHC class I gene. Blastocyst MHC has the structure of an MHC class I b gene, with the six exons characteristic of T-region genes. It is linked to H2-D. The amino acid sequence encoded by this gene maintains all the features of a functional antigen-presentation domain. The blastocyst MHC gene, like the human class I b gene HLA-G, is expressed at the blastocyst stage and in the placenta, and may be the mouse analog for HLA-G.