@article {152, title = {Rare A2ML1 variants confer susceptibility to otitis media.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Aug}, pages = {917-20}, abstract = {

A duplication variant within the middle ear-specific gene A2ML1 cosegregates with otitis media in an indigenous Filipino pedigree (LOD score = 7.5 at reduced penetrance) and lies within a founder haplotype that is also shared by 3 otitis-prone European-American and Hispanic-American children but is absent in non-otitis-prone children and >62,000 next-generation sequences. We identified seven additional A2ML1 variants in six otitis-prone children. Collectively, our studies support a role for A2ML1 in the pathophysiology of otitis media.

}, keywords = {alpha-Macroglobulins, Animals, Base Sequence, Child, Cochlea, Exome, Family Health, Female, Gene Duplication, Gene Frequency, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Male, Mice, Inbred C57BL, Models, Molecular, Otitis Media, Pedigree, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3347}, author = {Santos-Cortez, Regie Lyn P and Chiong, Charlotte M and Reyes-Quintos, Ma Rina T and Tantoco, Ma Leah C and Wang, Xin and Acharya, Anushree and Abbe, Izoduwa and Giese, Arnaud P and Smith, Joshua D and Allen, E Kaitlynn and Li, Biao and Cutiongco-de la Paz, Eva Maria and Garcia, Marieflor Cristy and Llanes, Erasmo Gonzalo D V and Labra, Patrick John and Gloria-Cruz, Teresa Luisa I and Chan, Abner L and Wang, Gao T and Daly, Kathleen A and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Patel, Janak A and Riazuddin, Saima and Sale, Michele M and Chonmaitree, Tasnee and Ahmed, Zubair M and Abes, Generoso T and Leal, Suzanne M} } @article {227, title = {Exome sequencing identifies a recurrent de novo ZSWIM6 mutation associated with acromelic frontonasal dysostosis.}, journal = {Am J Hum Genet}, volume = {95}, year = {2014}, month = {2014 Aug 07}, pages = {235-40}, abstract = {

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.

}, keywords = {Abnormalities, Multiple, Amino Acid Sequence, Animals, Base Sequence, Craniofacial Abnormalities, DNA Mutational Analysis, DNA-Binding Proteins, Exome, Face, Hedgehog Proteins, Humans, Intellectual Disability, Limb Deformities, Congenital, Mandibulofacial Dysostosis, Mice, Molecular Sequence Data, Mutation, Protein Structure, Tertiary, Zebrafish, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.07.008}, author = {Smith, Joshua D and Hing, Anne V and Clarke, Christine M and Johnson, Nathan M and Perez, Francisco A and Park, Sarah S and Horst, Jeremy A and Mecham, Brig and Maves, Lisa and Nickerson, Deborah A and Cunningham, Michael L} } @article {260, title = {Mutations in TJP2 cause progressive cholestatic liver disease.}, journal = {Nat Genet}, volume = {46}, year = {2014}, month = {2014 Apr}, pages = {326-8}, abstract = {

Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.

}, keywords = {Animals, Base Sequence, Cholestasis, Intrahepatic, High-Throughput Nucleotide Sequencing, Humans, Immunoblotting, Immunohistochemistry, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Biological, Molecular Sequence Data, Mutation, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Alignment, Species Specificity, Tight Junctions, Zonula Occludens-2 Protein}, issn = {1546-1718}, doi = {10.1038/ng.2918}, author = {Sambrotta, Melissa and Strautnieks, Sandra and Papouli, Efterpi and Rushton, Peter and Clark, Barnaby E and Parry, David A and Logan, Clare V and Newbury, Lucy J and Kamath, Binita M and Ling, Simon and Grammatikopoulos, Tassos and Wagner, Bart E and Magee, John C and Sokol, Ronald J and Mieli-Vergani, Giorgina and Smith, Joshua D and Johnson, Colin A and McClean, Patricia and Simpson, Michael A and Knisely, A S and Bull, Laura N and Thompson, Richard J} }