@article {473, title = {Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome.}, journal = {Am J Hum Genet}, volume = {102}, year = {2018}, month = {2018 06 07}, pages = {1126-1142}, abstract = {

The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that~perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in~any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune~phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.

}, keywords = {Base Sequence, Cell Line, Endoplasmic Reticulum Stress, Exons, Family, Frameshift Mutation, Genetic Predisposition to Disease, Heterozygote, Humans, Immunologic Deficiency Syndromes, Immunophenotyping, Infant, Newborn, Inflammation, Interferon Type I, Male, Molecular Chaperones, Mutant Proteins, Mutation, Nonsense Mediated mRNA Decay, Phenotype, Proteasome Endopeptidase Complex, RNA, Messenger, Syndrome, Unfolded Protein Response}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2018.04.010}, author = {Poli, M Cecilia and Ebstein, Fr{\'e}d{\'e}ric and Nicholas, Sarah K and de Guzman, Marietta M and Forbes, Lisa R and Chinn, Ivan K and Mace, Emily M and Vogel, Tiphanie P and Carisey, Alexandre F and Benavides, Felipe and Coban-Akdemir, Zeynep H and Gibbs, Richard A and Jhangiani, Shalini N and Muzny, Donna M and Carvalho, Claudia M B and Schady, Deborah A and Jain, Mahim and Rosenfeld, Jill A and Emrick, Lisa and Lewis, Richard A and Lee, Brendan and Zieba, Barbara A and K{\"u}ry, S{\'e}bastien and Kr{\"u}ger, Elke and Lupski, James R and Bostwick, Bret L and Orange, Jordan S} } @article {91, title = {Hutterite-type cataract maps to chromosome 6p21.32-p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death.}, journal = {Mol Genet Genomic Med}, volume = {4}, year = {2016}, month = {2016 Jan}, pages = {77-94}, abstract = {

BACKGROUND: Juvenile-onset cataracts are known among the Hutterites of North America. Despite being identified over 30~years ago, this autosomal recessive condition has not been mapped, and the disease gene is unknown.

METHODS: We performed whole exome sequencing of three Hutterite-type cataract trios and follow-up genotyping and mapping in four extended kindreds.

RESULTS: Trio exomes enabled genome-wide autozygosity mapping, which localized the disease gene to a 9.5-Mb region on chromosome 6p. This region contained two candidate variants, LEMD2 c.T38G and MUC21 c.665delC. Extended pedigrees recruited for variant genotyping revealed multiple additional relatives with juvenile-onset cataract, as well as six deceased relatives with both cataracts and sudden cardiac death. The candidate variants were genotyped in 84 family members, including 17 with cataracts; only the variant in LEMD2 cosegregated with cataracts (LOD~=~9.62). SNP-based fine mapping within the 9.5~Mb linked region supported this finding by refining the cataract locus to a 0.5- to 2.9-Mb subregion (6p21.32-p21.31) containing LEMD2 but not MUC21. LEMD2 is expressed in mouse and human lenses and encodes a LEM domain-containing protein; the c.T38G missense mutation is predicted to mutate a highly conserved residue within this domain (p.Leu13Arg).

CONCLUSION: We performed a genetic and genomic study of Hutterite-type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2.

}, issn = {2324-9269}, doi = {10.1002/mgg3.181}, author = {Boone, Philip M and Yuan, Bo and Gu, Shen and Ma, Zhiwei and Gambin, Tomasz and Gonzaga-Jauregui, Claudia and Jain, Mahim and Murdock, Todd J and White, Janson J and Jhangiani, Shalini N and Walker, Kimberly and Wang, Qiaoyan and Muzny, Donna M and Gibbs, Richard A and Hejtmancik, J Fielding and Lupski, James R and Posey, Jennifer E and Lewis, Richard A} } @article {271, title = {NR2F1 mutations cause optic atrophy with intellectual disability.}, journal = {Am J Hum Genet}, volume = {94}, year = {2014}, month = {2014 Feb 06}, pages = {303-9}, abstract = {

Optic nerve atrophy and hypoplasia can be primary disorders or can result from trans-synaptic degeneration arising from cerebral visual impairment (CVI). Here we report six individuals with CVI and/or optic nerve abnormalities, born after an uneventful pregnancy and delivery, who have either de novo heterozygous missense mutations in NR2F1, also known as COUP-TFI, or deletions encompassing NR2F1. All affected individuals show mild to moderate intellectual impairment. NR2F1 encodes a nuclear receptor protein that regulates transcription. A reporter assay showed that missense mutations in the zinc-finger DNA-binding domain and the putative ligand-binding domain decrease NR2F1 transcriptional activity. These findings indicate that NR2F1 plays an important role in the neurodevelopment of the visual system and that its disruption can lead to optic atrophy with intellectual disability.

}, keywords = {Adolescent, Adult, Amino Acid Sequence, Child, Child, Preschool, COUP Transcription Factor I, DNA-Binding Proteins, Female, Genotype, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Optic Atrophy, Phenotype, Young Adult, Zinc Fingers}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2014.01.002}, author = {Bosch, Dani{\"e}lle G M and Boonstra, F Nienke and Gonzaga-Jauregui, Claudia and Xu, Mafei and de Ligt, Joep and Jhangiani, Shalini and Wiszniewski, Wojciech and Muzny, Donna M and Yntema, Helger G and Pfundt, Rolph and Vissers, Lisenka E L M and Spruijt, Liesbeth and Blokland, Ellen A W and Chen, Chun-An and Lewis, Richard A and Tsai, Sophia Y and Gibbs, Richard A and Tsai, Ming-Jer and Lupski, James R and Zoghbi, Huda Y and Cremers, Frans P M and de Vries, Bert B A and Schaaf, Christian P} }