PUBLICATION

Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome

Authors
Ta-Shma, A., Khan, T.N., Vivante, A., Willer, J.R., Matak, P., Jalas, C., Pode-Shakked, B., Salem, Y., Anikster, Y., Hildebrandt, F., Katsanis, N., Elpeleg, O., Davis, E.E.
ID
ZDB-PUB-170321-3
Date
2017
Source
American journal of human genetics   100(4): 666-675 (Journal)
Registered Authors
Davis, Erica, Katsanis, Nicholas, Willer, Jason
Keywords
neurodevelopmental syndrome, splice isoforms, whole-exome sequencing
MeSH Terms
  • Abnormalities, Multiple/genetics*
  • Cardio-Renal Syndrome/genetics*
  • Child, Preschool
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Membrane Proteins/genetics*
  • Neurodevelopmental Disorders/genetics*
  • Pedigree
  • Point Mutation
  • Protein Isoforms/genetics
PubMed
28318500 Full text @ Am. J. Hum. Genet.
Abstract
Despite the accelerated discovery of genes associated with syndromic traits, the majority of families affected by such conditions remain undiagnosed. Here, we employed whole-exome sequencing in two unrelated consanguineous kindreds with central nervous system (CNS), cardiac, renal, and digit abnormalities. We identified homozygous truncating mutations in TMEM260, a locus predicted to encode numerous splice isoforms. Systematic expression analyses across tissues and developmental stages validated two such isoforms, which differ in the utilization of an internal exon. The mutations in both families map uniquely to the long isoform, raising the possibility of an isoform-specific disorder. Consistent with this notion, RT-PCR of lymphocyte cell lines from one of the kindreds showed reduced levels of only the long isoform, which could be ameliorated by emetine, suggesting that the mutation induces nonsense-mediated decay. Subsequent in vivo testing supported this hypothesis. First, either transient suppression or CRISPR/Cas9 genome editing of zebrafish tmem260 recapitulated key neurological phenotypes. Second, co-injection of morphants with the long human TMEM260 mRNA rescued CNS pathology, whereas the short isoform was significantly less efficient. Finally, immunocytochemical and biochemical studies showed preferential enrichment of the long TMEM260 isoform to the plasma membrane. Together, our data suggest that there is overall reduced, but not ablated, functionality of TMEM260 and that attenuation of the membrane-associated functions of this protein is a principal driver of pathology. These observations contribute to an appreciation of the roles of splice isoforms in genetic disorders and suggest that dissection of the functions of these transcripts will most likely inform pathomechanism.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes