ClinVar Genomic variation as it relates to human health

In a large white Brazilian family with amyotrophic lateral sclerosis (ALS8; 608627), Nishimura et al. (2004) found a heterozygous 166C-T transition in exon 2 of the VAPB gene, leading to a pro56-to-ser (P56S) mutation. Subsequently the authors demonstrated the same mutation in patients from 6 additional kindreds in which the clinical course varied, including some with late-onset spinal muscular atrophy (Finkel type; 182980) and some with typical severe ALS with rapid progression (see 105400). Although it was not possible to link all of these families, haplotype analysis suggested founder effect. In vitro functional expression studies in rat hippocampal neurons and HEK293 cells showed that the P56S mutation disrupted the normal subcellular distribution of the VAPB protein and caused intracellular aggregates. Unlike the wildtype protein, the mutant P56S protein did not colocalize with either the Golgi apparatus or the endoplasmic reticulum (ER). Nishimura et al. (2005) analyzed 7 polymorphic markers around the VAPB gene in an index case from each of the Brazilian families with P56S mutation previously reported by Nishimura et al. (2004) and in 9 Brazilian Portuguese controls. They found evidence for a common founder for all families regardless of ancestry, with a founding event 23 generations ago, consistent with the Portuguese colonization of Brazil. Teuling et al. (2007) found that the P56S mutant protein formed cytosolic aggregates in all cell types examined, including mouse and human nonneuronal cells. These aggregates did not colocalize with markers for the ER. Further studies showed that the mutant protein acted in a dominant-negative manner by recruiting wildtype VAPB to the aggregates and disrupting normal protein and cellular function. Landers et al. (2008) identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. The mutation was not identified in 79 additional ALS families. Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. Millecamps et al. (2010) suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century. De Vos et al. (2012) found that VAPB with the P56S mutation showed significantly higher affinity than wildtype for the outer mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). Increased binding with PTPIP51 resulted in accumulation of VAPB at mitochondria-associated membranes in the ER and elevated calcium uptake by mitochondria following release of calcium from ER stores. Expression of human VAPB with the P56S mutation also disturbed calcium handling in cultured rat cortical neurons following depolarization. Using cultured embryonic rat cortical neurons, Morotz et al. (2012) found that expression of human VAPB with the P56S mutation (VAPB-P56S) significantly slowed anterograde axonal transport of mitochondria. Studies in rat neurons and HEK293 cells showed that expression of VAPB-P56S increased resting intracellular Ca(2+) concentration and disrupted the interaction between tubulin (see 191130) and the mitochondrial membrane Rho GTPase MIRO1 (RHOT1; 613888). Expression of VAPB-P56S had no effect on the amount of TRAK1 (608112) or kinesin-1 (see 602809) associated with MIRO1. (less)

In a large white Brazilian family with amyotrophic lateral sclerosis (ALS8; 608627), Nishimura et al. (2004) found a heterozygous 166C-T transition in exon 2 of the VAPB gene, leading to a pro56-to-ser (P56S) mutation. Subsequently the authors demonstrated the same mutation in patients from 6 additional kindreds in which the clinical course varied, including some with late-onset spinal muscular atrophy (Finkel type; 182980) and some with typical severe ALS with rapid progression (see 105400). Although it was not possible to link all of these families, haplotype analysis suggested founder effect. In vitro functional expression studies in rat hippocampal neurons and HEK293 cells showed that the P56S mutation disrupted the normal subcellular distribution of the VAPB protein and caused intracellular aggregates. Unlike the wildtype protein, the mutant P56S protein did not colocalize with either the Golgi apparatus or the endoplasmic reticulum (ER). Nishimura et al. (2005) analyzed 7 polymorphic markers around the VAPB gene in an index case from each of the Brazilian families with P56S mutation previously reported by Nishimura et al. (2004) and in 9 Brazilian Portuguese controls. They found evidence for a common founder for all families regardless of ancestry, with a founding event 23 generations ago, consistent with the Portuguese colonization of Brazil. Teuling et al. (2007) found that the P56S mutant protein formed cytosolic aggregates in all cell types examined, including mouse and human nonneuronal cells. These aggregates did not colocalize with markers for the ER. Further studies showed that the mutant protein acted in a dominant-negative manner by recruiting wildtype VAPB to the aggregates and disrupting normal protein and cellular function. Landers et al. (2008) identified the P56S mutation in affected members of a Brazilian family with ALS. The mean age at onset was between 45 and 55 years with survival varying from 5 to 18 years. The mutation was not identified in 79 additional ALS families. Millecamps et al. (2010) identified the P56S mutation in 1 (0.6%) of 162 French probands with familial ALS. The patient was of Japanese descent, representing the first non-Brazilian reported to carry this mutation. Three other family members had motor neuron disease, suggesting autosomal dominant inheritance. The patient had long disease duration with onset in the legs during the sixth decade. Millecamps et al. (2010) suggested that the finding of the P56S mutation in a Japanese patient may reflect the Portuguese trading connection with the Far East and Brazil in the mid-16th century. De Vos et al. (2012) found that VAPB with the P56S mutation showed significantly higher affinity than wildtype for the outer mitochondrial membrane protein PTPIP51 (FAM82A2; 611873). Increased binding with PTPIP51 resulted in accumulation of VAPB at mitochondria-associated membranes in the ER and elevated calcium uptake by mitochondria following release of calcium from ER stores. Expression of human VAPB with the P56S mutation also disturbed calcium handling in cultured rat cortical neurons following depolarization. Using cultured embryonic rat cortical neurons, Morotz et al. (2012) found that expression of human VAPB with the P56S mutation (VAPB-P56S) significantly slowed anterograde axonal transport of mitochondria. Studies in rat neurons and HEK293 cells showed that expression of VAPB-P56S increased resting intracellular Ca(2+) concentration and disrupted the interaction between tubulin (see 191130) and the mitochondrial membrane Rho GTPase MIRO1 (RHOT1; 613888). Expression of VAPB-P56S had no effect on the amount of TRAK1 (608112) or kinesin-1 (see 602809) associated with MIRO1. (less)