@article {956, title = {Recurrent homozygous damaging mutation in , encoding a protein disulfide isomerase, in four families with microlissencephaly.}, journal = {J Med Genet}, volume = {57}, year = {2020}, month = {2020 04}, pages = {274-282}, abstract = {

BACKGROUND: Protein disulfide isomerase (PDI) proteins are part of the thioredoxin protein superfamily. PDIs are involved in the formation and rearrangement of disulfide bonds between cysteine residues during protein folding in the endoplasmic reticulum and are implicated in stress response pathways.

METHODS: Eight children from four consanguineous families residing in distinct geographies within the Middle East and Central Asia were recruited for study. All probands showed structurally similar microcephaly with lissencephaly (microlissencephaly) brain malformations. DNA samples from each family underwent whole exome sequencing, assessment for repeat expansions and confirmatory segregation analysis.

RESULTS: An identical homozygous variant in (c.500G>A), encoding thioredoxin-related transmembrane protein 2, segregated with disease in all four families. This variant changed the last coding base of exon 6, and impacted mRNA stability. All patients presented with microlissencephaly, global developmental delay, intellectual disability and epilepsy. While is an activator of cellular repeat expansion toxicity, patients showed no evidence of repeat expansions.

CONCLUSION: The c.500G>A allele associates with recessive microlissencephaly, and patients show no evidence of expansions. is the first PDI implicated in a recessive disease, suggesting a protein isomerisation defect in microlissencephaly.

}, keywords = {Amino Acid Sequence, Child, Child, Preschool, Consanguinity, Endoplasmic Reticulum, Exons, Female, Genetic Predisposition to Disease, Homozygote, Humans, Male, Membrane Proteins, Microcephaly, Mutation, Protein Disulfide-Isomerases, Protein Folding, Thioredoxins, Whole Exome Sequencing}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106409}, author = {Ghosh, Shereen Georges and Wang, Lu and Breuss, Martin W and Green, Joshua D and Stanley, Valentina and Yang, Xiaoxu and Ross, Danica and Traynor, Bryan J and Alhashem, Amal M and Azam, Matloob and Selim, Laila and Bastaki, Laila and Elbastawisy, Hanan I and Temtamy, Samia and Zaki, MAH and Gleeson, Joseph G} } @article {402, title = {Isolated polycystic liver disease genes define effectors of polycystin-1 function.}, journal = {J Clin Invest}, volume = {127}, year = {2017}, month = {2017 May 01}, pages = {1772-1785}, abstract = {

Dominantly inherited isolated polycystic liver disease (PCLD) consists of liver cysts that are radiologically and pathologically identical to those seen in autosomal dominant polycystic kidney disease, but without clinically relevant kidney cysts. The causative genes are known for fewer than 40\% of PCLD index cases. Here, we have used whole exome sequencing in a discovery cohort of 102 unrelated patients who were excluded for mutations in the 2 most common PCLD genes, PRKCSH and SEC63, to identify heterozygous loss-of-function mutations in 3 additional genes, ALG8, GANAB, and SEC61B. Similarly to PRKCSH and SEC63, these genes encode proteins that are integral to the protein biogenesis pathway in the endoplasmic reticulum. We inactivated these candidate genes in cell line models to show that loss of function of each results in defective maturation and trafficking of polycystin-1, the central determinant of cyst pathogenesis. Despite acting in a common pathway, each PCLD gene product demonstrated distinct effects on polycystin-1 biogenesis. We also found enrichment on a genome-wide basis of heterozygous mutations in the autosomal recessive polycystic kidney disease gene PKHD1, indicating that adult PKHD1 carriers can present with clinical PCLD. These findings define genetic and biochemical modulators of polycystin-1 function and provide a more complete definition of the spectrum of dominant human polycystic diseases.

}, keywords = {Adult, Animals, Cell Line, Transformed, Cysts, Endoplasmic Reticulum, Female, Genome-Wide Association Study, Glucosidases, Glucosyltransferases, Heterozygote, Humans, Intracellular Signaling Peptides and Proteins, Liver Diseases, Male, Membrane Proteins, Mice, Mutation, SEC Translocation Channels, TRPP Cation Channels}, issn = {1558-8238}, doi = {10.1172/JCI90129}, author = {Besse, Whitney and Dong, Ke and Choi, Jungmin and Punia, Sohan and Fedeles, Sorin V and Choi, Murim and Gallagher, Anna-Rachel and Huang, Emily B and Gulati, Ashima and Knight, James and Mane, Shrikant and Tahvanainen, Esa and Tahvanainen, Pia and Sanna-Cherchi, Simone and Lifton, Richard P and Watnick, Terry and Pei, York P and Torres, Vicente E and Somlo, Stefan} } @article {16, title = {Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Nov 03}, pages = {1005-1014}, abstract = {

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosome Mapping, Chromosomes, Human, Pair 12, Complement C1r, Complement C1s, Ehlers-Danlos Syndrome, Endoplasmic Reticulum, Exome, Female, Gene Deletion, Genetic Loci, Humans, Male, Mutation, Missense, Pedigree, Periodontitis, Protein Conformation, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.019}, author = {Kapferer-Seebacher, Ines and Pepin, Melanie and Werner, Roland and Aitman, Timothy J and Nordgren, Ann and Stoiber, Heribert and Thielens, Nicole and Gaboriaud, Christine and Amberger, Albert and Schossig, Anna and Gruber, Robert and Giunta, Cecilia and Bamshad, Michael and Bj{\"o}rck, Erik and Chen, Christina and Chitayat, David and Dorschner, Michael and Schmitt-Egenolf, Marcus and Hale, Christopher J and Hanna, David and Hennies, Hans Christian and Heiss-Kisielewsky, Irene and Lindstrand, Anna and Lundberg, Pernilla and Mitchell, Anna L and Nickerson, Deborah A and Reinstein, Eyal and Rohrbach, Marianne and Romani, Nikolaus and Schmuth, Matthias and Silver, Rachel and Taylan, Fulya and Vandersteen, Anthony and Vandrovcova, Jana and Weerakkody, Ruwan and Yang, Margaret and Pope, F Michael and Byers, Peter H and Zschocke, Johannes} } @article {173, title = {COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis.}, journal = {Nat Genet}, volume = {47}, year = {2015}, month = {2015 Jun}, pages = {654-60}, abstract = {

Unbiased genetic studies have uncovered surprising molecular mechanisms in human cellular immunity and autoimmunity. We performed whole-exome sequencing and targeted sequencing in five families with an apparent mendelian syndrome of autoimmunity characterized by high-titer autoantibodies, inflammatory arthritis and interstitial lung disease. We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain. Hypothesizing that mutant COPA leads to defective intracellular transport via coat protein complex I (COPI), we show that COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport. Additionally, expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response. Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity. Our findings uncover an unexpected molecular link between a vesicular transport protein and a syndrome of autoimmunity manifested by lung and joint disease.

}, keywords = {Amino Acid Sequence, Arthritis, Autoimmune Diseases, Child, Preschool, Coatomer Protein, Endoplasmic Reticulum, Endoplasmic Reticulum Stress, Female, Genetic Association Studies, Genetic Predisposition to Disease, Golgi Apparatus, HEK293 Cells, Humans, Infant, Lod Score, Lung Diseases, Interstitial, Male, Molecular Sequence Data, Pedigree, Protein Transport}, issn = {1546-1718}, doi = {10.1038/ng.3279}, author = {Watkin, Levi B and Jessen, Birthe and Wiszniewski, Wojciech and Vece, Timothy J and Jan, Max and Sha, Youbao and Thamsen, Maike and Santos-Cortez, Regie L P and Lee, Kwanghyuk and Gambin, Tomasz and Forbes, Lisa R and Law, Christopher S and Stray-Pedersen, Asbj{\o}rg and Cheng, Mickie H and Mace, Emily M and Anderson, Mark S and Liu, Dongfang and Tang, Ling Fung and Nicholas, Sarah K and Nahmod, Karen and Makedonas, George and Canter, Debra L and Kwok, Pui-Yan and Hicks, John and Jones, Kirk D and Penney, Samantha and Jhangiani, Shalini N and Rosenblum, Michael D and Dell, Sharon D and Waterfield, Michael R and Papa, Feroz R and Muzny, Donna M and Zaitlen, Noah and Leal, Suzanne M and Gonzaga-Jauregui, Claudia and Boerwinkle, Eric and Eissa, N Tony and Gibbs, Richard A and Lupski, James R and Orange, Jordan S and Shum, Anthony K} }