Bi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.

TitleBi-allelic Mutations in PKD1L1 Are Associated with Laterality Defects in Humans.
Publication TypeJournal Article
Year of Publication2016
AuthorsVetrini, F, D'Alessandro, LCA, Akdemir, ZC, Braxton, A, Azamian, MS, Eldomery, MK, Miller, K, Kois, C, Sack, V, Shur, N, Rijhsinghani, A, Chandarana, J, Ding, Y, Holtzman, J, Jhangiani, SN, Muzny, DM, Gibbs, RA, Eng, CM, Hanchard, NA, Harel, T, Rosenfeld, JA, Belmont, JW, Lupski, JR, Yang, Y
JournalAm J Hum Genet
Date Published2016 Oct 06
KeywordsAlleles, 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

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.

Alternate JournalAm J Hum Genet
PubMed ID27616478
PubMed Central IDPMC5065643
Grant ListT32 GM007526 / GM / NIGMS NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States

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