@article {24, title = {Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {886-893}, abstract = {

Disruption of the establishment of left-right (L-R) asymmetry leads to situs anomalies ranging from situs inversus totalis (SIT) to situs ambiguus (heterotaxy). The genetic causes of laterality defects in humans are highly heterogeneous. Via whole-exome sequencing (WES), we identified homozygous mutations in PKD1L1 from three affected individuals in two unrelated families. PKD1L1 encodes a polycystin-1-like protein and its loss of function is known to cause laterality defects in mouse and medaka fish models. Family 1 had one fetus and one deceased child with heterotaxy and complex congenital heart malformations. WES identified a homozygous splicing mutation, c.6473+2_6473+3delTG, which disrupts the invariant splice donor site in intron 42, in both affected individuals. In the second family, a homozygous c.5072G>C (p.Cys1691Ser) missense mutation was detected in an individual with SIT and congenital heart disease. The p.Cys1691Ser substitution affects a highly conserved cysteine residue and is predicted by molecular modeling to disrupt a disulfide bridge essential for the proper folding of the G protein-coupled receptor proteolytic site (GPS) motif. Damaging effects associated with substitutions of this conserved cysteine residue in the GPS motif have also been reported in other genes, namely GPR56, BAI3, and PKD1 in human and lat-1 in C.~elegans, further supporting the likely pathogenicity of p.Cys1691Ser in PKD1L1. The identification of bi-allelic PKD1L1 mutations recapitulates previous findings regarding phenotypic consequences of loss of function of the orthologous genes in mice and medaka fish and further expands our understanding of genetic contributions to laterality defects in humans.

}, keywords = {Alleles, Amino Acid Motifs, Amino Acid Sequence, Animals, Caenorhabditis elegans, Cysteine, Exome, Female, Fetal Diseases, Functional Laterality, Heart Defects, Congenital, Heterotaxy Syndrome, Homozygote, Humans, Infant, Newborn, Introns, Male, Membrane Proteins, Mice, Middle Aged, Models, Molecular, Mutation, Mutation, Missense, Oryzias, Pedigree, RNA Splicing, Situs Inversus}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.07.011}, author = {Vetrini, Francesco and D{\textquoteright}Alessandro, Lisa C A and Akdemir, Zeynep C and Braxton, Alicia and Azamian, Mahshid S and Eldomery, Mohammad K and Miller, Kathryn and Kois, Chelsea and Sack, Virginia and Shur, Natasha and Rijhsinghani, Asha and Chandarana, Jignesh and Ding, Yan and Holtzman, Judy and Jhangiani, Shalini N and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Hanchard, Neil A and Harel, Tamar and Rosenfeld, Jill A and Belmont, John W and Lupski, James R and Yang, Yaping} } @article {103, title = {Chimeric transcripts resulting from complex duplications in chromosome Xq28.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Feb}, pages = {253-6}, abstract = {

Gene fusions have been observed in somatic alterations in cancer and in schizophrenia. However, the underlying mechanism(s) for their formation are poorly understood. We experimentally demonstrated the expression of splicing variants of in silico predicted chimeric genes F8/CSAG1 and BCAP31/TEX28 in two individuals with de novo complex genomic rearrangements of Xq28; F8/CSAG1 includes exonization of an ERVL-MaLR intronic repetitive element. We provide evidence that replicative repair may contribute to exon shuffling processes and diversify the repertoire of expressed transcripts.

}, keywords = {Antigens, Neoplasm, Base Sequence, Cell Line, Chromosomes, Human, X, Exons, Gene Duplication, Gene Expression Regulation, Gene Rearrangement, Humans, Introns, Male, Membrane Proteins, Molecular Sequence Data, Neoplasm Proteins, RNA Splicing, RNA, Messenger, Transcription, Genetic}, issn = {1432-1203}, doi = {10.1007/s00439-015-1614-x}, author = {Zuccherato, Luciana W and Alleva, Benjamin and Whiters, Marjorie A and Carvalho, Claudia M B and Lupski, James R} } @article {108, title = {De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Dec 03}, pages = {904-13}, abstract = {

Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5{\textquoteright} end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(*)) and c.35_38delTCAA (p.Ile12Lysfs(*)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5{\textquoteright} end of the geminin protein. All three GMNN mutations identified alter sites 5{\textquoteright} to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS.

}, keywords = {Adolescent, Amino Acid Sequence, Base Sequence, Cell Cycle, Child, Preschool, Congenital Microtia, Dwarfism, Exons, Female, Geminin, Gene Expression, Genes, Dominant, Growth Disorders, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Inheritance Patterns, Male, Micrognathism, Molecular Sequence Data, Mutation, Patella, Pedigree, Protein Stability, Proteolysis, RNA Splicing, Sequence Alignment}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.006}, author = {Burrage, Lindsay C and Charng, Wu-Lin and Eldomery, Mohammad K and Willer, Jason R and Davis, Erica E and Lugtenberg, Dorien and Zhu, Wenmiao and Leduc, Magalie S and Akdemir, Zeynep C and Azamian, Mahshid and Zapata, Gladys and Hernandez, Patricia P and Schoots, Jeroen and de Munnik, Sonja A and Roepman, Ronald and Pearring, Jillian N and Jhangiani, Shalini and Katsanis, Nicholas and Vissers, Lisenka E L M and Brunner, Han G and Beaudet, Arthur L and Rosenfeld, Jill A and Muzny, Donna M and Gibbs, Richard A and Eng, Christine M and Xia, Fan and Lalani, Seema R and Lupski, James R and Bongers, Ernie M H F and Yang, Yaping} }