%0 Journal Article %J Am J Hum Genet %D 2016 %T Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans. %A Vetrini, Francesco %A D'Alessandro, Lisa C A %A Akdemir, Zeynep C %A Braxton, Alicia %A Azamian, Mahshid S %A Eldomery, Mohammad K %A Miller, Kathryn %A Kois, Chelsea %A Sack, Virginia %A Shur, Natasha %A Rijhsinghani, Asha %A Chandarana, Jignesh %A Ding, Yan %A Holtzman, Judy %A Jhangiani, Shalini N %A Muzny, Donna M %A Gibbs, Richard A %A Eng, Christine M %A Hanchard, Neil A %A Harel, Tamar %A Rosenfeld, Jill A %A Belmont, John W %A Lupski, James R %A Yang, Yaping %K Alleles %K Amino Acid Motifs %K Amino Acid Sequence %K Animals %K Caenorhabditis elegans %K Cysteine %K Exome %K Female %K Fetal Diseases %K Functional Laterality %K Heart Defects, Congenital %K Heterotaxy Syndrome %K Homozygote %K Humans %K Infant, Newborn %K Introns %K Male %K Membrane Proteins %K Mice %K Middle Aged %K Models, Molecular %K Mutation %K Mutation, Missense %K Oryzias %K Pedigree %K RNA Splicing %K Situs Inversus %X

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.

%B Am J Hum Genet %V 99 %P 886-893 %8 2016 Oct 06 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/27616478?dopt=Abstract %R 10.1016/j.ajhg.2016.07.011 %0 Journal Article %J Am J Hum Genet %D 2016 %T Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. %A Lalani, Seema R %A Liu, Pengfei %A Rosenfeld, Jill A %A Watkin, Levi B %A Chiang, Theodore %A Leduc, Magalie S %A Zhu, Wenmiao %A Ding, Yan %A Pan, Shujuan %A Vetrini, Francesco %A Miyake, Christina Y %A Shinawi, Marwan %A Gambin, Tomasz %A Eldomery, Mohammad K %A Akdemir, Zeynep Hande Coban %A Emrick, Lisa %A Wilnai, Yael %A Schelley, Susan %A Koenig, Mary Kay %A Memon, Nada %A Farach, Laura S %A Coe, Bradley P %A Azamian, Mahshid %A Hernandez, Patricia %A Zapata, Gladys %A Jhangiani, Shalini N %A Muzny, Donna M %A Lotze, Timothy %A Clark, Gary %A Wilfong, Angus %A Northrup, Hope %A Adesina, Adekunle %A Bacino, Carlos A %A Scaglia, Fernando %A Bonnen, Penelope E %A Crosson, Jane %A Duis, Jessica %A Maegawa, Gustavo H B %A Coman, David %A Inwood, Anita %A McGill, Jim %A Boerwinkle, Eric %A Graham, Brett %A Beaudet, Art %A Eng, Christine M %A Hanchard, Neil A %A Xia, Fan %A Orange, Jordan S %A Gibbs, Richard A %A Lupski, James R %A Yang, Yaping %K Alleles %K Arabs %K Arrhythmias, Cardiac %K Base Sequence %K Child %K Child, Preschool %K Endoplasmic Reticulum Stress %K Exome %K Exons %K Female %K Gene Deletion %K Golgi Apparatus %K Hispanic or Latino %K Homozygote %K Humans %K Infant %K Male %K Molecular Sequence Data %K Muscle Weakness %K Pedigree %K Rhabdomyolysis %K White People %X

The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

%B Am J Hum Genet %V 98 %P 347-57 %8 2016 Feb 04 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/26805781?dopt=Abstract %R 10.1016/j.ajhg.2015.12.008