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X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by the variations in the ATP-binding cassette sub-family D member 1 (ABCD1) gene. This study is the first to report central precocious puberty (CPP) in individuals with X-ALD. A 6-year-old boy exhibited mucocutaneous pigmentation, increased plasma adrenocorticotropic hormone levels, and elevated very long-chain fatty acids (VLCFA). We identified a variant, c.1826A>G (p. Glu609Gly), in exon 8 of the ABCD1 gene in the proband. Additionally, he displayed rapid growth, testicular volume of 5–6 mL, the onset of pubic hair, and pubertal levels of luteinizing hormone (LH), all meeting the diagnostic criteria for CPP.

Adrenoleukodystrophy protein (ALDP) is responsible for the transport of very-long-chain fatty acids (VLCFAs) and corresponding CoA-esters across the peroxisomal membrane. Dysfunction of ALDP leads to peroxisomal metabolic disorder exemplified by X-linked adrenoleukodystrophy (ALD). Hundreds of ALD-causing mutations have been identified on ALDP. However, the pathogenic mechanisms of these mutations are restricted to clinical description due to limited structural and biochemical characterization. Here we report the cryo-electron microscopy structure of human ALDP with nominal resolution at 3.4 Å. ALDP exhibits a cytosolic-facing conformation. Compared to other lipid ATP-binding cassette transporters, ALDP has two substrate binding cavities formed by the transmembrane domains. Such structural organization may be suitable for the coordination of VLCFAs. Based on the structure, we performed integrative analysis of the cellular trafficking, protein thermostability, ATP hydrolysis, and the transport activity of representative mutations. These results provide a framework for understanding the working mechanism of ALDP and pathogenic roles of disease-associated mutations.

The ABCD1 gene is a part of the ABC transporter family that encodes proteins involved in lipid and metabolite transport. Numerous non-synonymous single nucleotide polymorphisms (nsSNPs) have been identified within the coding region of the ABCD1 gene, some of which are associated with a rare genetic disorder X-linked adrenoleukodystrophy (ALD). However, the structural changes resulting from these nsSNPs remain poorly understood. This study utilized multiple bioinformatics tools to predict the high-risk pathogenic nsSNPs in ABCD1 and evaluate their potential impact on the structure and function of the adrenoleukodystrophy protein (ALDP). nsSNPs extracted from ENSEMBL and the Indian population-specific 1000 genomes project were analyzed using various in-silico tools to predict the pathogenic consequences of nsSNPs and their impact on physical, chemical, and structural changes in the protein. A total of 80 high-risk pathogenic nsSNPs (HRP_nsSNPs) were identified in ABCD1 which were predicted pathogenic, located at highly conserved residues with a conservation score of 9 and were associated with decreased protein stability. Notably, 3 novel nsSNPs specific to the Indian population were highlighted. These HRP_nsSNPs significantly affect amino acid properties such as size, charge, and hydrophobicity. Among the 80 HRP_nsSNPs, 60 have been previously linked to ALD, while 20 are newly identified. This study revealed that among thousands of nsSNPs, 80 were the HRP_nsSNPs that altered the physical and chemical properties of amino acids, led to structural changes in the protein, disruption of domain interactions, and impaired protein function. The work offers valuable insights for prioritizing pathogenic ABCD1 nsSNPs and studying the pathogenesis of ALD.

X‐linked adrenoleukodystrophy (X‐ALD) is caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC half‐transporter (ALDP) involved in the import of very long‐chain fatty acids (VLCFA) into the peroxisome. The disease is characterized by a striking and unpredictable variation in phenotypic expression. Phenotypes include the rapidly progressive childhood cerebral form (CCALD), the milder adult form, adrenomyeloneuropathy (AMN), and variants without neurologic involvement. There is no apparent correlation between genotype and phenotype. In males, unambiguous diagnosis can be achieved by demonstration of elevated levels of VLCFA in plasma. In 15 to 20% of obligate heterozygotes, however, test results are false–negative. Therefore, mutation analysis is the only reliable method for the identification of heterozygotes. Since most X‐ALD kindreds have a unique mutation, a great number of mutations have been identified in the ABCD1 gene in the last seven years. In order to catalog and facilitate the analysis of these mutations, we have established a mutation database for X‐ALD ( http://www.x‐ald.nl). In this review we report a detailed analysis of all 406 X‐ALD mutations currently included in the database. Also, we present 47 novel mutations. In addition, we review the various X‐ALD phenotypes, the different diagnostic tools, and the need for extended family screening for the identification of new patients. Hum Mutat 18:499–515, 2001. © 2001 Wiley‐Liss, Inc.

Background X-linked adrenoleukodystrophy (X-ALD; OMIM: 300100) is the most common peroxisomal disease caused by mutations in the ATP-binding cassette, sub-family D member 1 gene or ABCD1 (geneID: 215), the coding gene for the adrenoleukodystrophy protein (ALDP), which is an ATP-binding transport protein associated to an active transport of very long chain fatty acids (VLCFAs). Dysfunction of ALDP induces an accumulation of VLCFAs in all tissues leading to a neurodegenerative disorder that involves the nervous system white matter. Case presentation In our case report, magnetic resonance imaging (MRI) as well as the high levels of VLCFAs prompted the diagnosis the X-ALD. Molecular analysis of ABCD1 gene have shown a pathogenic homozygous nonsense mutation (c.1677C > G; p.(Tyr559*)) in exon 7. Conclusion Thus, we identified here a novel mutation in the ABCD1 gene in a Moroccan patient causing X-linked adrenoleukodystrophy.

X‐linked Adrenoleukodystrophy (X‐ALD) is the most frequent peroxisomal disease. It mainly involves the nervous system white matter, adrenal cortex and testes. Several distinct clinical phenotypes are known. The principal biochemical abnormality is the accumulation of saturated very‐long‐chain fatty acids (VLCFAs : > C22:0, mainly C26:0), which is due to impaired capacity for β‐oxidation in peroxisomes. Diagnosis is usually based on the VLCFA levels in plasma or cultured skin fibroblasts in both patients and carriers. In 0.1% of affected males, however, the plasma C26:0 level is borderline normal, and 15% of obligate female carriers have normal results. Effective mutation detection in these families is therefore fundamental to unambiguously determine the genetic status of each individual at risk. Of particular concern are female members of kindreds segregating X‐ALD mutations, because normal VLCFA levels do not guarantee lack of carrier status. We describe a fast method for detection of X‐ALD mutations. The method is based on SSCP analysis of nested PCR fragments followed by sequence‐determination reactions. Using this methodology we have found X‐ALD mutations in 30 kindreds, including 15 not previously reported. Hum Mutat 15:348–353, 2000. © 2000 Wiley‐Liss, Inc.

The adrenoleukodystrophy protein (ALDP) is a half-ABC (ATP-binding cassette) transporter localized in the peroxisomal membrane. Dysfunction of this protein is the cause of the human genetic disorder X-linked adrenoleukodystrophy (X-ALD), which is characterized by accumulation of saturated, very-long-chain fatty acids (VLCFAs). This observation suggests that ALDP is involved in the metabolism of these compounds. Whether ALDP transports VLCFAs or their derivatives across the peroxisomal membrane or some cofactors essential for the efficient peroxisomal β-oxidation of these fatty acids is still unknown. In this work, we used a protease-based approach to search for substrate-induced conformational alterations on ALDP. Our results suggest that ALDP is directly involved in the transport of long- and very-long-chain acyl-CoAs across the peroxisomal membrane.

X‐ALD is a neurological disorder associated with inherited defects in the ABCD1 (ALD) gene located on Xq28 and with impaired peroxisomal very long‐chain fatty acid β‐oxidation. We examined the ABCD1 gene in probands from 11 unrelated X‐ALD Czech and Slovak families by the direct sequencing of cDNA or genomic PCR products. In 10 families there were 10 different mutations, eight of which were novel. The spectrum of mutations consists of six point mutations, three microdeletions (1bp, 2bp, 4 bp), and one large deletion (229bp). In the 11th family we detected two novel single‐base pair substitutions in exon 1 (c.38 A>C and c.649 A>G), both causing amino acid exchanges (N13T and K217E). Expression studies revealed that only K217E is a deleterious mutation, because a plasmid encoding ALDP with K217E was ineffective in the restoration of defective β‐oxidation in X‐ALD fibroblasts. The N13T amino acid exchange, on the other hand, did not affect ALDP function. Thus, N13T represents the first polymorphism causing an amino acid exchange in the ABCD1 gene. As this polymorphism was observed neither in 100 control alleles nor in 300 X‐ALD patients who have been sequenced so far world‐wide, it seems to be very rare or unique. Two additional novel polymorphisms were found by the sequencing of the ABCD1 gene from our patients: c.–59 C/T in the 5′untranslated region and c.2019 C/T (F673F) in exon 10. The frequencies of these two polymorphisms, were 11/150 and 2/150 control alleles, respectively. Hum Mutat 18:52–60, 2001. © 2001 Wiley‐Liss, Inc.

3M has had a developmentally oriented, coaching‐based approach and philosophy with employees. Learning from experiences and from others is core to the 3M experience. The CEO of the company, Inge Thulin spends about one‐fifth of his time as CEO on talent, for example, teaching in leadership programs such as the Accelerated Leadership Development Program (ALDP) and the Emerging Leaders Program (ELP), and by directing pipeline development. The three roles at 3M that leaders play to assist in people's development and innovation are mentor, sponsor, and champion. 3M's talent process uses management team reviews (MTRs) to identify high potential or “top talent” leaders within each business. While there are no rigid, cookie‐cutter, step‐by‐step placements, 3M does have several types of placement opportunities that contribute to leadership development.