A human de novo mutation inMYH10phenocopies the loss of function mutation in mice

Abstract

We used whole exome sequence analysis to investigate a possible genetic etiology for a patient with the phenotype of intrauterine growth restriction, microcephaly, developmental delay, failure to thrive, congenital bilateral hip dysplasia, cerebral and cerebellar atrophy, hydrocephalus, and congenital diaphragmatic hernia (CDH). Whole exome sequencing identified a novel de novo c.2722G > T (p.E908X) mutation in the Myosin Heavy Chain 10 gene (MYH10) which encodes for non-muscle heavy chain II B (NMHC IIB). Mutations in MYH10 have not been previously described in association with human disease. The E908X mutation is located in the coiled-coil region of the protein and is expected to delete the tail domain and disrupt filament assembly. Nonmuscle myosin IIs (NM IIs) are a group of ubiquitously expressed proteins, and NM II B is specifically enriched in neuronal tissue and is thought to be important in neuronal migration. It is also expressed in cardiac myocytes along with NM IIC. Homozygous NMHC II B-/B- mouse knockouts die by embryonic day (E)14.5 with severe cardiac defects (membranous ventricular septal defect and cardiac outflow tract abnormalities) and neurodevelopmental disorders (progressive hydrocephalus and neuronal migrational abnormalities). A heterozygous MYH10 loss of function mutation produces a severe neurologic phenotype and CDH but no apparent cardiac phenotype and suggests that MYH10 may represent a novel gene for brain malformations and/or CDH.

Proteomic Analysis of Brain Region and Sex-Specific Synaptic Protein Expression in the Adult Mouse Brain

“…Also, the murine variant of the non-muscle heavy chain II B, encoded by the Myosin Heavy Chain 10 gene (MYH10) was found to be less expressed in the synapse from the male hippocampus. In humans, mutation of MYH10 leads to a severe CNS phenotype characterized by microcephaly, cerebral and cerebellar atrophy and severe intellectual disability [89]. The gene encoding the protein SET, which showed increased expression level in the cortical synapse in female mice, is listed as strong ASD candidate (category 2) in the SFARI autism gene database.…”

The role of vertebrate nonmuscle Myosin II in development and human disease

“…These abnormalities are consistent with the fact that NM II-B is the most prominent isoform of NM II expressed in cardiac myocytes and the nervous system. Tuzovic et al 81 used whole exomic sequence analysis to search for a possible genetic defect in an 8 y old male who was born after intrauterine growth restriction and who showed evidence of microcephaly, developmental delay, hydrocephalus, cerebral and cerebellar atrophy and a congenital diaphragmatic hernia. Whole exomic sequencing identified a novel heterozygous mutation, E908X in MYH10, the gene encoding NMHC II-B.…”

Genetic causes of congenital diaphragmatic hernia

“…MYH10 mutations have been identified in two children with CDH. One child had an apparently isolated CDH and passed away in the neonatal period, and the other child had multiple congenital anomalies and intellectual disability [105]. It is anticipated that, with recent advances in comprehensive genomic sequencing technology, additional genes will be identified in both isolated and non-isolated CDH, providing further insight into this genetically heterogeneous condition.…”