S149R, a novel mutation in the ABCD1 gene causing X-linked adrenoleukodystrophy.

Fang Yan,Jing Chen,Hui Ying,Hongyu Li,Wenbo Wang,Chao Xu

doi:10.18632/oncotarget.20974

Abstract

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is a heterogeneous disorder caused by mutations in the ATP-binding cassette protein subfamily D1 (ABCD1) gene, encoding the peroxisomal membrane protein ALDP, which is involved in the transmembrane transport of very long-chain fatty acids. For the first time, we report a case of olivopontocerebellar X-ALD on the Chinese mainland. In this study, a novel mutation (c.447T>A; p.S149R) in ABCD1 was detected in a patient diagnosed with X-ALD. The mutant amino acid is well conserved among species. Bioinformatics analysis predicted the substitution to be deleterious and to cause structural changes in the adrenoleukodystrophy protein. Immunofluorescence showed an altered subcellular localization of the S149R mutant protein, which may lead to defects in the degradation of very long chain fatty acids in peroxisomes. We therefore suggest that the novel mutation, which alters ALDP structure, subcellular distribution and function, is responsible for X-ALD.

Highlights

X-linked adrenoleukodystrophy (X-ALD; MIM: #300100) is the most common inherited peroxisomal disorder characterized by neurodegeneration and adrenal insufficiency
X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. It is a heterogeneous disorder caused by mutations in the ATP-binding cassette protein subfamily D1 (ABCD1) gene, encoding the peroxisomal membrane protein adrenoleukodystrophy protein (ALDP), which is involved in the transmembrane transport of very long-chain fatty acids
The patient was subjected to examinations, including laboratory tests, brain magnetic resonance imaging (MRI) and abdominal computed tomography (CT)

Summary

Introduction

X-linked adrenoleukodystrophy (X-ALD; MIM: #300100) is the most common inherited peroxisomal disorder characterized by neurodegeneration and adrenal insufficiency. X-ALD is classified as cerebral ALD (childhood, adolescent and adult forms), adrenomyeloneuropathy (AMN), Addison-only (AO), olivopontocerebellar ALD and asymptomatic ALD. In heterozygous females, it is categorized into mild myelopathy, moderate to severe myeloneuropathy, cerebral involvement, clinically evident adrenal insufficiency and asymptomatic ALD [4]. Except for cerebral ALD and AMN, olivopontocerebellar ALD is an exceedingly rare form (1-2% of ALD cases), which is characterized by cerebellar and brainstem involvement in adolescence or adulthood [4].

Methods

Results

Conclusion