Multigenic truncation of the semaphorin-plexin pathway by a germline chromothriptic rearrangement associated with Moebius syndrome.

Abstract

Moebius syndrome (MBS) is a congenital disorder caused by paralysis of the facial and abducens nerves. Although a number of candidate genes have been suspected, so far only mutations in PLXND1 and REV3L are confirmed to cause MBS. Here, we fine mapped the breakpoints of a complex chromosomal rearrangement (CCR) 46,XY,t(7;8;11;13) in a patient with MBS, which revealed 41 clustered breakpoints with typical hallmarks of chromothripsis. Among 12 truncated protein-coding genes, SEMA3A is known to bind to the MBS-associated PLXND1. Intriguingly, the CCR also truncated PIK3CG, which in silico interacts with REVL3 encoded by the other known MBS-gene REV3L, and with the SEMA3A/PLXND1 complex via FLT1. Additional studies of other complex rearrangements may reveal whether the multiple breakpoints in germline chromothripsis may predispose to complex multigenic disorders.

• Authors: Lusine Nazaryan-Petersen, Inês R Oliveira, Mana M Mehrjouy, Juan M M Mendez, Mads Bak, Merete Bugge, Vera M Kalscheuer, Iben Bache, Dustin C Hancks, Niels Tommerup
• Journal: Human mutation (Hum Mutat) Vol. 40 Issue 8 Pg. 1057-1062 (08 2019) ISSN: 1098-1004 [Electronic] United States
• PMID: 31033088 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Wiley Periodicals, Inc.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Membrane Glycoproteins
• PLXND1 protein, human
• SEMA3A protein, human
• Semaphorin-3A
• Semaphorins

Topics

• Chromosome Breakpoints
• Chromothripsis
• Fatal Outcome
• Gene Rearrangement
• Germ-Line Mutation
• High-Throughput Nucleotide Sequencing
• Humans
• Intracellular Signaling Peptides and Proteins (genetics)
• Male
• Membrane Glycoproteins (genetics)
• Middle Aged
• Mobius Syndrome (genetics)
• Semaphorin-3A (genetics)
• Semaphorins (genetics)