Novel FIG4 mutations in Yunis–Varon syndrome

Abstract

Yunis-Varon syndrome (YVS, MIM 216340) is a rare autosomal recessive disorder characterized by skeletal abnormalities and severe neurological impairment with vacuolation of the central nervous system, skeletal muscles and cartilages. Very recently, mutations of the FIG4 (FIG4 homolog, SAC1 lipid phosphatase domain containing (Saccharomyces cerevisiae)) gene, which encodes a 5'-phosphoinositide phosphatase essential for endosome/lysosome function have been identified as the cause for YVS. Interestingly, FIG4 mutations were previously reported to be responsible for other neurodegenerative diseases such as autosomal recessive Charcot-Marie-Tooth disease type 4J and autosomal dominant amyotrophic lateral sclerosis/primary lateral sclerosis. We analyzed a YVS patient using whole-exome sequencing, and identified novel biallelic FIG4 mutations: c.1750+1delG and c.2284_2285delCT (p.S762Wfs*3). These two mutations were mutations supposed to have null function. To our knowledge, this is the second report of FIG4 mutations in YVS and our result supports the idea that biallelic null mutations of FIG4 cause YVS in human.

Yunis-Varón syndrome caused by biallelic VAC14 mutations

“…2,13 The spectrum of described neurological manifestations in YVS is very broad, including pachygyria, polymicrogyria, callosal and/or cerebellar vermis hypoplasia, Dandy-Walker malformation, ventriculomegaly, hydrocephalus, and white matter atrophy. 2,6,13,14 As far as we are aware, the MRI and magnetic resonance spectroscopy findings in our patient (leukodystrophy, spectroscopic changes, and cystic basal ganglial degeneration) are previously-unreported, comparable clinical reports being few. It remains to be seen whether the latter findings are VAC14-specific, or a general feature of YVS irrespective of genotype.…”

The Protein Complex of Neurodegeneration-related Phosphoinositide Phosphatase Sac3 and ArPIKfyve Binds the Lewy Body-associated Synphilin-1, Preventing Its Aggregation

“…The neuropathology in patients with familial Parkinsonism, in addition to a nigral neuronal loss and the presence of widespread Lewy bodies in the brainstem or cerebral cortex, is characterized by vacuolation within the temporal lobe and lower neurons (61)(62)(63). Notably, the known FIG/SAC3-linked neurological disorders in humans or mice (pale tremor mice) are all triggered by Sac3 deficiency and are associated with neuronal vacuolation or the accumulation of electron-dense inclusion bodies in different cell types (5,9,14,15,40). Consistently, we also observed increased cytoplasmic inclusions of Sph1 upon Sac3 depletion in both neuronal and non-neuronal cells (Fig.…”

“…Sac3 deficiency has also been implicated as a pathogenic cause and/or a risk factor in other heritable neurological disorders such as amyotrophic lateral sclerosis, with heterozygous null mutations (11)(12)(13), Yunis-Varon syndrome, with biallelic null mutations and complete loss of Sac3 (14,15), and bilateral temporo-occipital polymicrogyria, with homozygous A783V missense mutation (16) within the ArPIKfyve-binding region (2). The ubiquitous presence of the endogenous PAS complex in mammalian tissues and cells (3,17) together with the ubiquitous ArPIKfyve/Sac3 protein distribution (3,18,19) raises the question as to how Sac3 deficiency in both patients and genetically modified null mice results in predominant neuronal defects, whereas other organs remain largely unaffected.…”

Defective phosphoinositide metabolism in autism

“…FIG4, for instance, which dephosphorylates PI(3,5)P 2 to PI(3)P but also functions as an activator of the PI(3)P 5-kinase PIKfyve (Bharadwaj et al, 2016), is mutated in a severe form of Charcot-Marie-Tooth disease, CMT4J (Chow et al, 2007). Mutations in FIG4 were also found in Yunis-Varon syndrome, a neurological disorder with skeletal defects and severe neuronal loss in the central nervous system (Nakajima et al, 2013), as well as in some forms of amyloid lateral sclerosis, although a causal link has not yet been proved (Chow et al, 2009). Last but not least and as discussed above, FIG4 is part of the PIKfyve complex, which has been shown to be regulated by APP and, thus, may play a role in Alzheimer's disease (Currinn et al, 2015;Currinn and Wassmer, 2016).…”