Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis

Abstract

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/ deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis

“…Thus, perturbation of intracellular signaling associated with accumulation of active Lyn in chorea-acanthocytosis erythrocytes can generate acanthocytes and might be a sign of impaired quality control mechanisms for cellular protein. This is in agreement with the reported reduction in haptoglobin levels in chorea-acanthocytosis patients, 3 suggesting that abnormal Lynmediated signal transduction might impact in vivo red cell homeostasis in chorea-acanthocytosis subjects.…”

“…[4][5][6] However, despite progress toward elucidation of the molecular defects responsible for choreaacanthocytosis, the functional contribution of chorein deficiency to chorea-acanthocytosis remains unclear. 2,3 Chorein is present in normal mature erythrocytes, but it is partially or completely absent in chorea-acanthocytosis red cells. 1,7,8 Studies comparing the human VPS13A gene product, chorein, with homologs in other organisms such as yeast and Dictyostelium discoideum suggest possible involvement of chorein in trafficking of transmembrane proteins or in vesicular sorting systems directing cargo to the prevacuolar compartment (comparable to the human late endosome).…”

Chorein Sensitivity of Actin Polymerization, Cell Shape and Mechanical Stiffness of Vascular Endothelial Cells

“…In human umbilical vein endothelial cells, decreased chorein expression markedly reduced the filamentous actin network which led to a distinct change in cell morphology with more prominent lamellipodium and softening of those cells. Furthermore, loss of chorein leads to caspase 3 activation and decreases survival of the human umbilical vein endothelial cells .The present observations provide compelling evidence that chorein is not only important for erythrocyte shape and neuronal function [3,6,7,8,9] but may be effective in a wide variety of further functions.…”

“…Loss of function mutations [5] of the VPS13A gene [6,7,8,9] leads to chorea-acanthocytosis (ChAc), an autosomal recessive genetic disease characterized by progressive hyperkinetic movement disorder with muscle dystrophy cognitive dysfunction, behavioural abnormalities, chronic hyperkalemia and variable acanthocytosis of red blood cells [5,10]. Clinically overt disease develops at an age between 30 and 70 years and progresses to disability and premature death [10].…”

Applications of high-throughput DNA sequencing to benign hematology

“…Multiple genetic loci are involved and include mutations in chorein (VPS13A) in ChAc, XK (XK) in MLS, junctophilin-3 (JPH3) in HDL2, and pantothenate kinase 2 (PANK2) in PKAN. [19][20][21] Most NA mutations are private, that is, each kindred has a unique mutation, making mutation detection difficult, and several of the NA genes are very large, making traditional Sanger sequencing cumbersome. Walker and colleagues used exome sequencing to identify compound heterozygous mutations of the VPS13A gene in 2 NA patients, allowing precise genetic diagnosis and providing information for genetic counseling of affected patients and their family members.…”