ABCD1 p.Lys276Glu
| Predicted by SNAP2: | A: D (85%), C: D (91%), D: D (91%), E: D (85%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), L: D (91%), M: D (91%), N: D (85%), P: D (95%), Q: D (85%), R: D (71%), S: D (80%), T: D (85%), V: D (91%), W: D (95%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, L: D, M: D, N: D, P: D, Q: D, R: N, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Altered expression of ALDP in X-linked adrenoleuko... Am J Hum Genet. 1995 Aug;57(2):292-301. Watkins PA, Gould SJ, Smith MA, Braiterman LT, Wei HM, Kok F, Moser AB, Moser HW, Smith KD
Altered expression of ALDP in X-linked adrenoleukodystrophy.
Am J Hum Genet. 1995 Aug;57(2):292-301., [PMID:7668254]
Abstract [show]
X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disorder with variable phenotypic expression that is characterized by elevated plasma and tissue levels of very long-chain fatty acids. However, the product of the gene defective in ALD (ALDP) is a membrane transporter of the ATP-binding cassette family of proteins and is not related to enzymes known to activate or oxidize fatty acids. We generated an antibody that specifically recognizes the C-terminal 18 amino acids of ALDP and can detect ALDP by indirect immunofluorescence. To better understand the mechanism by which mutations in ALDP lead to disease, we used this antibody to examine the subcellular distribution and relative abundance of ALDP in skin fibroblasts from normal individuals and ALD patients. Punctate immunoreactive material typical of fibroblast peroxisomes was observed in cells from seven normal controls and eight non-ALD patients. Of 35 ALD patients tested, 17 had the childhood-onset cerebral form of the disease, 13 had the milder adult phenotype adrenomyeloneuropathy, 3 had adrenal insufficiency only, and 2 were affected fetuses. More than two-thirds (69%) of all patients studied showed no punctate immunoreactive material. There was no correlation between the immunofluorescence pattern and clinical phenotype. We determined the mutation in the ALD gene in 15 of these patients. Patients with either a deletion or frameshift mutation lacked ALDP immunoreactivity, as expected. Four of 11 patients with missense mutations were also immunonegative, indicating that these mutations affected the stability or localization of ALDP. In the seven immunopositive patients with missense mutations, correlation of the location and nature of the amino acid substitution may provide new insights into the function of this peroxisomal membrane protein. Furthermore, the study of female relatives of immunonegative ALD probands may aid in the assessment of heterozygote status.
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176 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2.................. AMN 870-2AGAGE291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P+ 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2.
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ABCD1 p.Lys276Glu 7668254:176:394
status: NEW178 In 11 patients, missense mutations that occurred throughout the protein were found: within the transmembrane domains (patients 1, 3, and 4), within the ATP-binding domain (patients 8-12), and on either side of the ATP-binding Table 3 Mutational Analysis of the ALD Gene in IS Unrelated Patients ALDP Patient Phenotype Mutation Consequence Immunoreactivity 1 .................. CALD 825 A-GG K276E + 2 .................. AMN 870-2 AGAG E291,& 3 .................. CALD 872 G-C E291D 4 .................. AMN 1023 T-IC S342P + 5 .................. AMN 1166 G-C R389H + 6 .................. CALD 1201 G-AA R401Q + 7 ........ CALD 1415-6 AAG FS@472 8 ........ AMN 1771 G-AA R591Q + 9 ........ Addison 1817 C-T S606L + 10 ................ AMN 1850 G-AA R617H 11 ................ CALD 1876 G-AA A626T 12 ................ Fetus 1884 G-C D629H + 13 ................ CALD 1932 C-UT Q645X 14 ................ AMN 1978 C-OT R660W 15 ........ AMN AExon7-10 Null Mutations in the ALD gene were determined, as described in Methods, in 15 of the ALD patients reported in table 2.
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ABCD1 p.Lys276Glu 7668254:178:394
status: NEW[hide] Molecular diagnosis of X-linked adrenoleukodystrop... Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12. Lan F, Wang Z, Xie H, Huang L, Ke L, Yang B, Zhu Z
Molecular diagnosis of X-linked adrenoleukodystrophy: experience from a clinical genetic laboratory in mainland China with report of 13 novel mutations.
Clin Chim Acta. 2011 May 12;412(11-12):970-4. Epub 2011 Feb 12., [PMID:21300044]
Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by progressive demyelination of the nervous system, adrenocortical insufficiency and increase of very long chain fatty acids (VLCFAs) in the plasma and tissues. METHODS: A total of 131 individuals from 30 Chinese pedigrees were involved in this study, including 42 symptomatic patients, 44 female carriers, and 15 high-risk fetuses from 13 families. The mutation was first pinpointed through long distance RT-PCR-based RNA approach and confirmed through peripheral blood DNA approach. RESULTS: A total of 28 mutations were identified, of which 19 were missense, 3 nonsense and 6 frame-shift mutations. Thirteen mutations were novel, i.e. p.R280L, p.P580L, p.G343V, p.S108X, p.R259W, p.P534R, p.fs A246, p.L576P, p.K602X, p.A314P, p.N148D, p.H283R, and p.fs R89. Two mutations occurred de novo, for they were not found in somatic cells of their parents. Three females from the same family developed AMN-like symptoms and they were heterozygous for the p.H283R mutation. Four asymptomatic boys were diagnosed as X-ALD patients and prenatal molecular diagnosis were provided for 13 X-ALD-stricken families. CONCLUSIONS: Our work extended the spectrum of mutations in X-ALD and benefited genetic counseling through reliable identification of heterozygous females and asymptomatic males.
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99 Pedigree Number of patient Number of carriere Phenotype of patient Base change Amino acid change Position of mutation Feature of mutation Prenatal diagnosis 1 1 2 AdolCALD 1225GNT R280L Exon 1 Missense 2 1 1 CCALD 1909CNT P508L Exon 6 Missense 3 4 3 CCALD 1987CNG P534R Exon 6 Missense Y 4 1 1 CCALD 1182GNA G266R Exon 1 Missense 5 1a +1b 1 CCALD 2235CNG R617G Exon 8 Missense Y 6 1+1a +1c 1 CCALD 1414GNT G343V Exon 2 Missense 7 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift 8 1+1b 1 CCALD 2235CNT R617C Exon 8 Missense Yh 9 1 1 CCALD 2065CNT P560L Exon 7 Y 10 1+1a 2+1b CCALD [709 NA; 1161CNT] [S108X; R259W] Exon 1 Nonsense; Missense Y 11 1 1 CCALD 1126ins GCCATCG fs I246 Exon 1 Frameshift 12 1 1 CCALD 2113TNC L576P Exon 7 Missense 13 1a +2c 3 CCALD 807GNA A141T Exon 1 Missense 14 1 1 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 15 1 1+1b CCALD 915CNA Q177X Exon 1 Nonsense Yh 16 1+1a 1 CCALD 1588GNA R401Q Exon 3 Missense 17 1 1 CCALD 1212 ANG K276E Exon 1 Missense Y 18 1 1 CCALD 907 ANG Y174C Exon 1 Missense 19 1 2 CCALD 2190 ANT K602X Exon 8 Nonsense 20 1 1 CCALD 1326GNC A314P Exon 2 Missense 21 1 1 CCALD 828 ANG N148D Exon 1 Missense Y 22 1 1 CCALD 1588GNA R401Q Exon 3 Missense Y 23 1 0f CCALD 2278GNA C631Y Exon 9 Missense 24 1a 1 CCALD 1008insG fs S207 Exon 1 Frameshift Y 25 1 0f CCALD 1920GNA G512S Exon 6 Missense 26 1+1c 3 CCALD 1415_02 del AG fs E471 Exon 5 Frameshift Y 27 1+1b 1 CCALD [1035ANG; 1853GNA] [K217E; V489V] Exon 1 Missense; same sense Y 28 1+3d 4 AMNg 1234ANG H283R Exon 1 Missense 29 1+2a 3 CCALD 1233CNG H283D Exon 1 Missense 30 2 3 AMN; CCALD 656_57 delGA fs R89 Exon 1 Frameshift a patient or proband died at the time of referral; b fetus by prenatal diagnosis; c presymptomatic at the time of referral; d female heterozygote patient; e determined by molecular ananlysis or deduced by the fact that the carrier was the daughter of an X-ALD, or the mother of at least one X-ALD patients; f de novo mutation; g including three heterozygote female patients; h twice for two pregnancies.
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ABCD1 p.Lys276Glu 21300044:99:961
status: NEW[hide] A rapid and sensitive protocol for prenatal molecu... Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26. Lan F, Wang Z, Ke L, Xie H, Huang L, Huang H, Tu X, Zheng D, Zeng J, Li H, Xin N, Yang B
A rapid and sensitive protocol for prenatal molecular diagnosis of X-linked adrenoleukodystrophy.
Clin Chim Acta. 2010 Dec 14;411(23-24):1992-7. Epub 2010 Aug 26., [PMID:20800589]
Abstract [show]
BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative genetic disease characterized by progressive demylination of the brain, adrenal insufficiency and elevated VLCFA level. ABCD1gene is the disease gene and more than 500 unique mutations in the ABCD1gene have been recorded in the database, approximately 60% of which are noncurrent ones. Although great progress has been made in the treatment of X-ALD, prenatal diagnosis is still badly needed by X-ALD-stricken families. METHODS: Twelve high-risk fetuses entered this study. Amniotic fluid (AF) was divided into two parts, with one part being used directly to isolate genomic DNA and debris from the other part for amniotic fluid cells (AFC) culturing. STR profiling was performed to evaluate maternal contamination of AFC genomic DNA. Two different molecular approaches, be they any two of direct sequencing, PCR-RFLP, ARMS, dot hybridization and DHPLC, were applied to determine whether the mutation identified in the index patient was found in the fetus. RESULTS: The genotypes of all 12 fetuses were determined, among which 2 were diagnosed as ALD males, 5 unaffected males, 1 heterozygote, and 4 normal unaffected females. A total of 9 families sent samples of umbilical blood at the time of delivery, and results of molecular checking of these samples agreed with those of prenatal diagnosis. Up until now, no ALD-related abnormalities were reported postnatally. CONCLUSION: An in-house protocol for the prenatal molecular diagnosis of X-ALD was established, and this protocol would provide accurate and rapid prenatal genetic service to X-ALD-stricken families.
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No. Sentence Comment
74 Family Origin (province) Genotype of proband Age (years) of carrier at amniocentesis Weeks of pregnancy at amniocentesis 1 Guangdong p.Arg617Gly 39 28 2 Shandong p.Pro534Arg 25 21 3 Fujian p.Arg617Cys 33(34)a 16(17)a 4 Hebei 1415_1416delAG (p.Glu471fs) 29 26 5 Fujian [p.Ser108X; p.Arg259Trp] 33 19 6 Shandong p.Pro560Leu 35 18 7 Anhui p.Gln177X 33 20 8 Shandong p.Lys276Glu 33 16 9 Hubei p.Asn148Asp 35 18 10 Jilin c.622_623insG (p.Ser207fs) 35 16 11 Guangxi p.Arg401Gln 32 16 a Figures in parentheses represent those data of second-time prenatal diagnosis for another fetus from family 3.
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ABCD1 p.Lys276Glu 20800589:74:365
status: NEW103 Fetus 9: The PCR product of 269 bp, spanning the site of p. Lys276Glu mutation, from the AFC's DNA of fetus 9 showed an elution profile similar to that of its father in DHPLC (Fig. 4, F9).
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ABCD1 p.Lys276Glu 20800589:103:60
status: NEW