@article {157, title = {Mutation of ATF6 causes autosomal recessive achromatopsia.}, journal = {Hum Genet}, volume = {134}, year = {2015}, month = {2015 Sep}, pages = {941-50}, abstract = {

Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans.

}, keywords = {Activating Transcription Factor 6, Adolescent, Animals, Asian Continental Ancestry Group, Color Vision Defects, Consanguinity, DNA Mutational Analysis, Exome, Female, Frameshift Mutation, Genotyping Techniques, Homozygote, Humans, Limit of Detection, Male, Mice, Mice, Inbred C57BL, Pakistan, Pedigree, Phenotype, Retina, Signal Transduction}, issn = {1432-1203}, doi = {10.1007/s00439-015-1571-4}, author = {Ansar, Muhammad and Santos-Cortez, Regie Lyn P and Saqib, Muhammad Arif Nadeem and Zulfiqar, Fareeha and Lee, Kwanghyuk and Ashraf, Naeem Mahmood and Ullah, Ehsan and Wang, Xin and Sajid, Sundus and Khan, Falak Sher and Amin-ud-Din, Muhammad and Smith, Joshua D and Shendure, Jay and Bamshad, Michael J and Nickerson, Deborah A and Hameed, Abdul and Riazuddin, Saima and Ahmed, Zubair M and Ahmad, Wasim 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 {254, title = {TCIRG1-associated congenital neutropenia.}, journal = {Hum Mutat}, volume = {35}, year = {2014}, month = {2014 Jul}, pages = {824-7}, abstract = {

Severe congenital neutropenia (SCN) is a rare hematopoietic disorder, with estimated incidence of 1 in 200,000 individuals of European descent, many cases of which are inherited in an autosomal dominant pattern. Despite the fact that several causal genes have been identified, the genetic basis for >30\% of cases remains unknown. We report a five-generation family segregating a novel single nucleotide variant (SNV) in TCIRG1. There is perfect cosegregation of the SNV with congenital neutropenia in this family; all 11 affected, but none of the unaffected, individuals carry this novel SNV. Western blot analysis show reduced levels of TCIRG1 protein in affected individuals, compared to healthy controls. Two unrelated patients with SCN, identified by independent investigators, are heterozygous for different, rare, highly conserved, coding variants in TCIRG1.

}, keywords = {DNA Mutational Analysis, Heterozygote, Humans, Mutation, Neutropenia, Pedigree, Vacuolar Proton-Translocating ATPases}, issn = {1098-1004}, doi = {10.1002/humu.22563}, author = {Makaryan, Vahagn and Rosenthal, Elisabeth A and Bolyard, Audrey Anna and Kelley, Merideth L and Below, Jennifer E and Bamshad, Michael J and Bofferding, Kathryn M and Smith, Joshua D and Buckingham, Kati and Boxer, Laurence A and Skokowa, Julia and Welte, Karl and Nickerson, Deborah A and Jarvik, Gail P and Dale, David C} }