ATP8A2-related disorders as recessive cerebellar ataxia

Abstract

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Novel variants in critical domains of ATP8A2 and expansion of clinical spectrum

“…The effect of the p.Met438Val variant on ATP8A2 expression and activity was reported in another paper during the preparation of this manuscript and shown to express at low levels and be devoid of PS-dependent ATPase activity (Guissart et al, 2020).…”

“…The first human disorder associated with a genetic defect in ATP8A2 was reported in a patient with a t(10;13) de novo balanced translocation, resulting in intellectual disability (ID) and severe hypotonia (Cacciagli et al, 2010). Since then, a number of loss of function ATP8A2 variants have been shown to be responsible for ID, severe hypotonia, and other neurological phenotypes (Alsahli et al, 2018;Choi et al, 2019;Emre Onat et al, 2013;Guissart et al, 2020;Martín-Hernández et al, 2016;McMillan et al, 2018).…”

A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4

“…Altogether, 6 of the 7 homozygous or compound heterozygous missense mutations known in ATP8A2 located in this subregion (amino acids 364‐877) of the catalytic cytoplasmic domain. These mutations highly reduced the expression of ATP8A2 gene, probably due to significant misfolding together with proteasomal degradation 15 . Protein misfolding may change the fundamental residues involved in protein interactions.…”

“…These mutations highly reduced the expression of ATP8A2 gene, probably due to significant misfolding together with proteasomal degradation. 15 Protein misfolding may change the fundamental residues involved in protein interactions. According to STRING, GeneMANIA, and literature review,…”

“…The previous literature has described 32 patients from different ethnicities with ATP8A2 mutations and phenotypic features assigned to CAMRQ4. Almost all of these mutations have been located in the cytoplasmic region that includes phosphorylation (P), nucleotide‐binding (N), and actuator (A) domains 15 …”