Disruption of the ATP8A2 gene in a patient with a t(10;13) de novo balanced translocation and a severe neurological phenotype

Abstract

Mental retardation is a frequent condition that is clinically and genetically highly heterogeneous. One of the strategies used to identify new causative genes is to take advantage of balanced chromosomal rearrangements in affected patients. We characterized a de novo t(10;13) balanced translocation in a patient with severe mental retardation and major hypotonia. We found that the balanced translocation is molecularly balanced. The translocation breakpoint disrupts the coding sequence of a single gene, called ATP8A2. The ATP8A2 gene is not ubiquitously expressed, but it is highly expressed in the brain. In situ hybridization performed in mouse embryos at different stages of development with the mouse homologue confirms this observation. A total of 38 patients with a similar phenotype were screened for mutations in the ATP8A2 gene but no mutations were found. The balanced translocation identified in this patient disrupts a single candidate gene highly expressed in the brain. Although this chromosomal rearrangement could be the cause of the severe phenotype of the patient, we were not able to identify additional cases. Extensive screening in the mentally retarded population will be needed to determine if ATP8A2 haploinsufficiency or dysfunction causes a neurological phenotype in humans.

Critical roles of isoleucine-364 and adjacent residues in a hydrophobic gate control of phospholipid transport by the mammalian P4-ATPase ATP8A2

“…Mutation of ATP8A2 was recently identified as the cause of the CAMRQ syndrome in a Turkish family (22), who are the first reported patients with a disease-causing point mutation in ATP8A2. Previously, a patient with severe mental retardation and major hypotonia had been reported to carry a de novo balanced translocation of chromosomes 10 and 13 disrupting the coding sequence of the ATP8A2 gene (27). Moreover, wabbler-lethal mice with inactivating deletion or insertion mutations of ATP8A2 have been found to develop severe neurological abnormalities such as ataxia and body tremors, due to distal axonal degeneration in spinal neurons (28).…”

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

“…The protein is highly expressed in newborn and embryonic tissues, with strongest expression in mouse heart, brain and testis. 10,28 RT-PCR analysis revealed similar expression in different regions of the human brain. 10 To evaluate the possible involvement of ATP8A2 in motor functions, we examined its expression profile in different human brain regions by quantitative real-time RT-PCR.…”

“…10,28 RT-PCR analysis revealed similar expression in different regions of the human brain. 10 To evaluate the possible involvement of ATP8A2 in motor functions, we examined its expression profile in different human brain regions by quantitative real-time RT-PCR. Human ATP8A2 is expressed in all brain regions with the highest level of expression in cerebellum (Figure 3).…”

“…We report herein that a recessive missense mutation in ATP8A2, encoding ATPase, aminophospholipid transporter, class I, type 8A, member 2, is associated with the phenotype in Family C. In an independent study, a de novo t(10;13) balanced translocation disrupting the coding sequence of ATP8A2 on 13q12 was observed in a patient with severe mental retardation and major hypotonia, raising the possibility that haploinsufficiency of this gene could be implicated in neurodevelopmental phenotypes. 10 On the basis of these observations, we suggest that ATP8A2 could be critically important in the development of the nervous system.…”

Lipid flippase modulates olfactory receptor expression and odorant sensitivity in Drosophila

“…Defects in ATP8B1 expression cause progressive familial intrahepatic cholestasis type 1 (12,17). Lesions in ATP8A1 are associated with abnormalities in the developing nervous system (12,16,(18)(19)(20). Sixteen P4-type ATPases are encoded in the human genome, and six are present in the Drosophila genome, but the function of the majority of these proteins is unknown.…”