Mutations in DOCK7 in Individuals with Epileptic Encephalopathy and Cortical Blindness

Abstract

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.

A novel truncating mutation of DOCK7 gene with an early-onset non-encephalopathic epilepsy

“…As a stop gain mutation locates in exon 27, post-transcriptional mRNA quality control mechanism (nonsense mediated decay) eliminates the mRNA of DOCK7 containing this premature termination codon. Similarly, the reported 4 compound heterozygote mutations are located in upstream exons, and are proposed as having the potential to induce nonsense-mediated decay of the corresponding mRNA [3]. Our patient gained some developmental skills with regard to motor and limited nonverbal interactions, but the presence of some autistic features and lack of verbal skills imply a specific clinical picture associated with truncating mutations of DOCK7.…”

Spontaneous mutation of Dock7 results in lower trabecular bone mass and impaired periosteal expansion in aged female Misty mice

“…Although, we did not find an increase in resorption at 52 wks dynamically or by bone turnover markers/gene expression in our study, it remains unclear whether higher SNS tone is responsible for the non-cell autonomous effects on bone with age in m/m [43]. In fact, Dock7 has been studied for its role in brain and nervous system [8, 9, 14, 18, 19, 44, 45], but it remains unclear if any of these alterations in the nervous system may affect bone development or remodeling. Propranolol treatment, a β2AR antagonist, has been shown to partially rescue m/m bone phenotype in young mice, suggesting that the SNS may indeed be contributing to bone loss in the m/m [4].…”

“…Humans homozygous for mutations in the Dock7 gene display signs of epilepsy, intellectual disability and cortical blindness [19]. Changes in bone metabolism have yet to be explored in this population.…”

Novel Genes of Early-Onset Epileptic Encephalopathies: From Genotype to Phenotypes

“…38 The same patients had an abnormally marked pontobulbar sulcus and occipital lobe T2 hyperintensities and atrophy at the magnetic resonance. 38 Guanine nucleotide-binding protein, alpha-activating activity polypeptide o number 1 (GNAO1; OMIM number 139311)…”