Missense mutation in the ATPase, aminophospholipid transporter protein ATP8A2 is associated with cerebellar atrophy and quadrupedal locomotion

Abstract

Cerebellar ataxia, mental retardation and dysequilibrium syndrome is a rare and heterogeneous condition. We investigated a consanguineous family from Turkey with four affected individuals exhibiting the condition. Homozygosity mapping revealed that several shared homozygous regions, including chromosome 13q12. Targeted next-generation sequencing of an affected individual followed by segregation analysis, population screening and prediction approaches revealed a novel missense variant, p.I376M, in ATP8A2. The mutation lies in a highly conserved C-terminal transmembrane region of E1 E2 ATPase domain. The ATP8A2 gene is mainly expressed in brain and development, in particular cerebellum. Interestingly, an unrelated individual has been identified, in whom mental retardation and severe hypotonia is associated with a de novo t(10;13) balanced translocation resulting with the disruption of ATP8A2. These findings suggest that ATP8A2 is involved in the development of the cerebrocerebellar structures required for posture and gait in humans.

Pharmacogenetic Discovery in CALGB (Alliance) 90401 and Mechanistic Validation of a VAC14 Polymorphism that Increases Risk of Docetaxel-Induced Neuropathy

“…The P-type ATPases are a superfamily of proteins that translocate phospholipids between the two leaflets of cellular lipid bilayers(45). Several lines of evidence link ATP8A2 to neurological development and function; in vitro data that ATP8A2 overexpression enhances neurite outgrowth(46), animal data that ATP8A2 mutations cause overt progressive neurodegeneration in Wabbler-lethal mice by disrupting axonal transport and polarity(47), and case reports of ATP8A2 mutations causing severe neurological phenotypes in patients(48, 49). …”

P4 ATPases: Flippases in Health and Disease

“…However, screening of an additional 37 patients with a similar phenotype did not result in the identification of ATP8A2 mutations. Additionally, a recessive missense mutation in ATP8A2 was detected in three members of a consanguineous family affected with cerebellar ataxia, mental retardation and disequilibrium syndrome (CAMRQ) [106]. Although only a small number of patients have been identified with mutations in ATP8A2 it seems likely that it is a risk factor for neurodegenerative diseases.…”

Decoding P4-ATPase substrate interactions

“…Mutations in one of these hydrophobic residues (I364, ATP8A2) were capable of changing the apparent K m of the enzyme (Vestergaard et al , 2014). This residue is of particular interest because an I364M mutation causes neurological disease in humans (Onat et al , 2013), and the analogous residue in cation pumps (Glu) is part of the canonical binding site. These targeted analyses were used to propose a “Hydrophobic Gate” model of substrate transport, hypothesizing that the vertical pumping of TM4 controls an internal hydrophobic gate that alternates water penetration from opposite sides of the membrane to achieve directional transport.…”