Molecular diagnosis of X-linked adrenoleukodystrophy: Experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations

Lan, Fenghua; Wang, Zhihong; Xie, Haihua; Huang, Lianghu; Ke, Long-feng; Yang, Bo-sheng; Zhu, Zhongyong

doi:10.1016/j.cca.2011.01.036

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…15,16 The third VUS, observed in patient 4, had an allele frequency greater than expected for a pathogenic variant (23 of 12 877 alleles in the African population, including 7Figure 2. Follow-up Protocol for Screen-Positive Specimens…”

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confidence: 92%

Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina

et al. 2020

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IMPORTANCE X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal genetic disorder in which an accumulation of very long-chain fatty acids leads to inflammatory demyelination in the central nervous system and to adrenal cortex atrophy. In 2016, X-ALD was added to the US Recommended Uniform Screening Panel. OBJECTIVETo evaluate the performance of a single-tier newborn screening assay for X-ALD in North Carolina. DESIGN, SETTING, AND PARTICIPANTSThis diagnostic screening study was of all newborn dried blood spot specimens received in the North Carolina State Laboratory of Public Health between January 2 and June 1, 2018, excluding specimens of insufficient quantity or quality. A total of 52 301 specimens were screened for X-ALD using negative ionization high-performance liquid chromatography tandem mass spectrometry to measure C24:0-and C26:0-lysophosphatidylcholine concentrations. Sanger sequencing of the adenosine triphosphate-binding cassette subfamily D member 1 (ABCD1) gene was performed on screen-positive specimens.EXPOSURES A medical and family history, newborn physical examination, sequencing of ABCD1 on dried blood spot samples, and plasma analysis of very long-chain fatty acids were obtained for all infants with screen-positive results. MAIN OUTCOMES AND MEASURESThe prevalence of X-ALD in North Carolina and the positive predictive value and false-positive rate for the first-tier assay were determined. RESULTSOf 52 301 infants tested (47.8% female, 50.6% male, and 1.7% other or unknown sex), 12 received screen-positive results. Of these 12 infants, 8 were confirmed with a genetic disorder: 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, 1 female infant with a peroxisome biogenesis disorder, and 1 female infant with Aicardi-Goutières syndrome. Four infants were initially classified as having false-positives results, including 3 female infants who were deemed unaffected and 1 male infant with indeterminate results on confirmatory testing. The positive predictive value for X-ALD or other genetic disorders for the first-tier assay was 67%, with a false-positive rate of 0.0057%. CONCLUSIONS AND RELEVANCEThis newborn screening pilot study reported results on 2 lysophosphatidylcholine analytes, identifying 3 male infants with X-ALD, 3 X-ALD-heterozygous female infants, and 3 infants with other disorders associated with increased very long-chain fatty acids. These results showed successful implementation in a public health program with minimal risk (continued) Key Points Question What is the analytical and clinical validity of a mass spectrometric method evaluating very long-chain fatty acyl-lysophosphatidylcholine species for the detection of X-linked adrenoleukodystrophy among newborns in North Carolina? Findings In this newborn diagnostic screening study of 52 301 dried blood spot specimens, 3 male infants were confirmed to have X-linked adrenoleukodystrophy, 3 female infants were identified as heterozygous for X-linked adrenoleukodystrophy (carriers), 1 female infant had a peroxisome biogenesis...

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confidence: 92%

Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina

et al. 2020

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“…The inner helix of TM4 on separated TM bundles only moves close to each other in the outward-facing conformation and R280 on both helix forms salt bridge interaction at the very bottom of the outward-opening vestibule. Mutation of R280 to Cystine may lock the protein in an outward-facing conformation (Coll et al, 2005;Lan et al, 2011), further structural studies of R280C will be needed to clarify its in uence on the function of the protein. A large number of cases have been reported at the S606 and G512 position from signature motif and the Walker A motif respectively (Gartner et al, 2002;Kumar et al, 2011;Zhang et al, 2011), which interacts with the ATP molecule at the outward facing conformation.…”

Section: Discussionmentioning

confidence: 99%

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

Tang

Chao

Jia

et al. 2021

Preprint

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The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 Å and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.

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“…The inner helix of TM4 on separated TM bundles only moves close to each other in the outward-facing conformation and R280 on both helix forms salt bridge interaction at the very bottom of the outward-opening vestibule. Mutation of R280 to Cystine may lock the protein in an outward-facing conformation (Coll et al, 2005;Lan et al, 2011), further structural studies of R280C will be needed to clarify its influence on the function of the protein. A large number of cases have been reported at the S606 and G512 position from signature motif and the Walker A motif respectively (Gartner et al, 2002;Kumar et al, 2011;Zhang et al, 2011), which interacts with the ATP molecule at the outward facing conformation.…”

Section: Structural Basis Of Disease-causing Mutationsmentioning

confidence: 99%

“…Although the mutant of ABCD1 contributes the accumulation of long-chain fatty acids (VLCFAs) caused by damaged peroxisome β-oxidation to affect the stability of adrenal gland, testis and myelin (Wang et al, 2011), the full information on the ABCD1 structure is lack from enough experimental evidences also. Previously, given knowledge showed that the substrate of ABCD1, as straight-chain saturated fatty acids (Wiesinger et al, 2013), was confirmed at transfection of human ABCD1 reverse transcription DNA into X-ALD skin fibroblasts to restore the oxidative activity of VLCFA β and the VLCFA content in fibroblasts to normal (Braiterman et al, 1998;Flavigny et al, 1999), it was therefore designated as the transporter of VLCFA through the membrane of peroxisome and dependent on the β-oxidation pathway (Kawaguchi et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

Chao

Jia

Shen

et al. 2021

Preprint

View full text Add to dashboard Cite

The malfunction of ABCD1 causes X-linked adrenoleukodystrophy (X-ALD), a rare neurodegenerative disease that affect all tissues in human. Residing in the peroxisome membrane, ABCD1 plays a role in the translocation of very long chain fatty acids (VLCFA) for their damage by β-oxidation. Here, we present five Cryo-Electron microscopy structures of ABCD1 in four conformational states. Combined with functional analysis, we found that substrate and ATP trigger the closing of two nucleotide binding domains (NBDs) over a distance of 40 &Aring and the rearrangement of the transmembrane domains. Each of the three inward-facing structure of ABCD1 has a vestibule opens to cytosol with variable size. Furthermore, the structure of ABCD1 in the outward-facing state supports that ATP molecules pull the two NBDs together and open the transmembrane domain to the peroxisomal lumen for substrate release. The five structures provide a snapshot of substrate transporting cycle and mechanistic implications for disease-causing mutations.

show abstract

Molecular diagnosis of X-linked adrenoleukodystrophy: Experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations

Cited by 8 publications

References 27 publications

Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina

Evaluation of X-Linked Adrenoleukodystrophy Newborn Screening in North Carolina

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

ATP and Substrate Binding Regulates Conformational Changes of Human Peroxisomal ABC Transporter ALDP

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