ABCMdb

PMID: 21889498

Shukla P, Gupta N, Gulati S, Ghosh M, Vasisht S, Sharma R, Gupta AK, Kalra V, Kabra M
Molecular analysis of ABCD1 gene in Indian patients with X-linked adrenoleukodystrophy.
Clin Chim Acta. 2011 Nov 20;412(23-24):2289-95. Epub 2011 Aug 26., [PubMed]

Sentences

No. Mutations Sentence Comment

55 ABCD1 p.Arg401Gln Prenatal diagnosis Prenatal diagnosis was done in one family having an affected child with c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene by CV sample taken at 12 weeks of gestation. CSGE was done for exon 3 of ABCD1 gene followed by sequencing to confirm the results. Login to comment 68 ABCD1 p.Arg401Gln ABCD1 p.Pro560Leu ABCD1 p.Leu516Pro ABCD1 p.Arg660Gln Six reported mutations, c.1202 GNA (p.Arg401Gln), c.1679 CNT (p.Pro560Leu), c.1816 TNC (p.Ser606Pro), 1547 TNC (p. Leu516Pro), c.1780+2 TNG (p.Gly593fs), c.1979 GNA (p.Arg660Gln) were found in eight patients (Fig. 1a, b, c and d). Login to comment 69 ABCD1 p.Pro560Leu ABCD1 p.Arg660Gln All mutations were unique except two, c.1679 CNT (p.Pro560Leu) and c.1979 GNA (p. Arg660Gln) which were found in two unrelated families. Login to comment 73 ABCD1 p.Pro560Leu ABCD1 p.Leu516Pro ABCD1 p.Arg660Gln Data analysis Results of data analysis done by PolyPhen tool for the missense mutations found in X-ALD patients showed all missense changes, c.1202 GNA (p.Arg401Gln), c.1679 CNT (p.Pro560Leu), c.1816 TNC (p.Ser606Pro), c.1547 TNC (p.Leu516Pro) c.1979 GNA (p.Arg660Gln) as probably damaging (Table 3). Login to comment 75 ABCD1 p.Arg401Gln ABCD1 p.Arg401Gln Prenatal diagnosis of X-ALD Prenatal diagnosis was done in one family having an affected child with c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene by CV sample taken at 12 weeks of gestation. CSGE analysis of exon 3 of CV sample showed no mobility shift, suggesting that the CV sample was negative for c.1202 GNA (p.Arg401Gln) change (Fig. 2a). Login to comment 90 ABCD1 p.Arg401Gln Missense mutation, c.1202 GNA (p.Arg401Gln) is located in "hinge" region between the transmembrane and ATP binding domains, which is a conserved region and thus supposed to be pathogenic. Login to comment 93 ABCD1 p.Pro560Leu Another missense mutation c.1679 CNT (p.Pro560Leu), lies between Walker A and B# motifs of ALDP protein, which are the conserved regions of the protein [7]. Login to comment 103 ABCC7 p.Ser549Arg ABCC7 p.Ser549Ile The CFTR mutants p.Ser549Ile, p.Ser549Arg, that involve the same amino acid position as in the ALD mutant fail to produce mature CFTR and therefore prevent trafficking to the correct cellular localization [18]. Login to comment 105 ABCD1 p.Leu516Pro The missense change, 1547 TNC (p.Leu516Pro) in exon 6 was also reported by other groups (unpublished data, www.x-ald.nl). Login to comment 110 ABCD1 p.Arg660Gln The mutation, c.1979 GNA (p.Arg660Gln) was found in exon 9 in two patients (A16 and A18), along with two other synonymous changes, p.Ala650Ala, and p.Ser633Ser in both patients. Login to comment 123 ABCD1 p.Arg401Gln ABCD1 p.Pro560Leu Patients Age of onset (Years) Age at diagnosis (Years) Clinical features Phenotype Mutation/polymorphisma PolyPhen results PSIC score difference A1 8 8 Neuroregression, seizures, deterioration of hearing, behavior problem, cognitive decline, frequent falls CCER c.1202 GNA (p.Arg401Gln) in exon 3 3.071 Probably damaging A2b 7.7 8 Neuroregression, deterioration of hearing, deterioration of school performance, behavior problem, cognitive decline, speech problem, abnormal gait CCER No A3b 26 27 Hyperactivity, behavior problem, abnormal gait AMN c.1679 CNT (p.Pro560Leu) in exon 7 3.379 Probably damaging A4 3 6 Neuroregression, deterioration of vision, deterioration of school performance, can't ambulate. Login to comment 124 ABCD1 p.Pro560Leu ABCD1 p.Arg660Gln ABCD1 p.Arg660Gln ABCD3 p.Leu516Pro CCER No A5b 34 39 Neuroregression, behavior problem, speech problem, abnormal gait, urinary incontinence AMN c.1679 CNT (p.Pro560Leu) in exon7/c.420 CNA (p.Ile140Ile) (unreported) in exon 1 A6 13 15 Hyperactivity, slurred speech, spastic gait, deterioration of vision AMN No A7b 22 26 Neuroregression, deterioration of vision, cognitive decline, aggressive behavior, spastic gait, urinary incontinence Adult Cerebral c.1938_1939dupGG (p.Ala647fs) in exon 9 A8 4 4.5 Deterioration of vision and hearing, delayed micturition CCER No A9 6 6 Neuroregression, deterioration of vision and hearing, behavior problem, slurred speech, abnormal gait CCER c.1816 TNC (p.Ser606Pro) in exon 8 2.499 Probably damaging A10b 8 8 Neroregression, deterioration of vision, cognitive decline, speech problem, spastic gait CCER c.1394-2ANG in intron 4 A11 15 22 Neuroregression, seizures, deterioration of vision, cognitive decline, speech problem, spastic gait Adolescent c.67_83del17 (p.Ala23fs) in exon 1 A12b 20 21 Neuroregression, speech problem, abnormal gait, urinary incontinence AMN c.1547 TNC (p.Leu516Pro) in exon 6 2.482 Probably damaging A13 45.5 46 Neuroregression, spastic paraparesis, deterioration of vision and hearing, memory decine, behavior problem, cognitive decline, impotence, urinary incontinence Adult cerebral c.1780+2 TNG in exon 7 A14 11 11 Neuroregression, deterioration of hearing, deterioration of school performance, behavior problem, gait abnormaility Adolescent No A15 9 12 Loss of vision and hearing, low volume speech CCER c.395 GNA (p.Trp132X) in exon 1 A16 1 14 Neuroregression, seizures, deterioration of school performance, behavioral problem CCER c.1979 GNA (p.Arg660Gln) in exon 9/p.Ala650Ala, p. Ser633Ser in exon 9 2.409 Probably damaging A17b 0.3 9 Seizures, weakness of right limbs, speech problem, abnormal gait CCER No A18 0.9 15 Neuroregression, deterioration of vision and hearing, behavioral problem, cognitive decline, speech problem, abnormal gait CCER c.1979 GNA (p.Arg660Gln) in exon 9/p.Ala650Ala, p. Ser633Ser in exon 9 2.409 Probably damaging A19 0.6 14 Loss of vision and hearing, speech problem CCER No/p.Ser633Ser in exon 9 A20 12 14 Spastic quadriparaparesis, mild cognitive decline, delayed puberty AMN No CCER: Childhood Cerebral. Login to comment 131 ABCD1 p.Arg401Gln a. CSGE gel showing shift in exon 3 in patint A1 and electropherogram showing c.1202 GNA (p.Arg401Gln) mutation. Login to comment 132 ABCD1 p.Leu516Pro b. CSGE gel showing shift in exon 6 in patient A12 and electropherogram showing c.1547 TNC (p.Leu516Pro) mutation. Login to comment 133 ABCD1 p.Pro560Leu c. CSGE gel showing shift in exon 7 in patients A3 and A5 and electropherogram showing c.1679 CNT (p.Pro560Leu) mutation. Login to comment 142 ABCD1 p.Pro560Leu ABCD1 p.Arg660Gln Most of the mutations found in our study were unique to the kindreds except two missense mutations, c.1679 CNT (p.Pro560Leu) in exon 7 (found A3 and A5) and c.1979 GNA (p.Arg660Gln) in exon 9 (found in A16 and A18) of the ABCD1 gene. Login to comment 159 ABCD1 p.Arg401Gln In our study, c.1202 GNA (p.Arg401Gln) mutation was found in the affected child having childhood cerebral phenotype while others reported them in patients with AMN and CCER phenotype [7,14]. Login to comment 160 ABCD1 p.Pro560Leu Similarly the mutation c.1679 CNT (p.Pro560Leu) was observed in AMN patient in our study, but Takano et al. reported this mutation in childhood cerebral phenotype and Feigenbaum and coworkers reported it in four patients, three having childhood cerebral phenotype and one having AMN phenotype with cerebral involvement [7,8]. Login to comment 166 ABCD1 p.Arg401Gln ABCD1 p.Arg660Gln This phenotype was found in patients with splice site mutation, insertion and nonsense mutation as well as patients having missense mutations, c.1202 GNA (p.Arg401Gln), c.1816 TNC (p.Ser606Pro) and c.1979 GNA (p.Arg660Gln) (Table 4). Login to comment 170 ABCD1 p.Arg401Gln A1 is sample of affected child showing shift in exon 3 for the c.1202 GNA (p.Arg401Gln) of ABCD1 gene. Login to comment 173 ABCD1 p.Arg401Gln Electropherogram showing CV DNA normal for c.1202 GNA (p.Arg401Gln) mutation in exon 3 of ABCD1 gene. Login to comment 175 ABCD1 p.Arg401Gln Electropherogram showing heterozygous mutation, c.1202 GNA (p.Arg401Gln) in exon 3 of ABCD1 gene in mother of patient A1. Login to comment 176 ABCD1 p.Pro560Leu Although the mild phenotype, adrenomyeloneuropathy was present in second group of missense mutations, but in a patient with AMN (A3) phenotype having the mutation, c.1679 CNT (p.Pro560Leu) had two sibs who had early onset of same illness with visual loss, seizures, stiffness, paraparesis and had expired at an early age of 8 years. Login to comment