Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX).

Kim, Kyoung-Sook; Kubota, Shunichim; Kuriyama, Masaru; Fujiyama, Jiro; Björkhem, Ingemar; Eggertsen, Gösta; Seyama, Yousuke

doi:10.1016/s0022-2275(20)40096-3

Cited by 61 publications

(17 citation statements)

References 21 publications

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Section: Discussionmentioning

confidence: 64%

“…The two mutations found in this study had been separately reported . One missense mutation, p.R474W (formerly called R441W), was reported in typical patients and one atypically late‐onset patient, suggesting that the phenotype of this mutation may vary considerably. Another mutation, the exonic mutation IVS2ds‐12G>T, did not change the encoded amino acid (silent mutation), but created a cryptic splice site, led to loss of 13 bases, and caused a frameshift thereafter (Figure D) .…”

Section: Discussionmentioning

confidence: 64%

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Neurologic findings are the sole manifestations of a patient with cerebrotendinous xanthomatosis

Yamashita

Hirano

Yanagimoto

et al. 2019

Neurology & Clinical Neurosc

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Cerebrotendinous xanthomatosis (CTX), a treatable autosomal recessive lipid‐storage disease, is caused by mutations in the CYP27A1 gene. Clinical manifestations include progressive neurologic dysfunction, tendon xanthoma, cataracts, and diarrhea. Patients with CTX generally have several non‐neurologic signs and symptoms, and thus, patients with only neurologic findings have been rarely reported. We here report a patient who solely had neurologic findings with compound heterozygous mutations in the CYP27A1 gene.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 64%

Neurologic findings are the sole manifestations of a patient with cerebrotendinous xanthomatosis

Yamashita

Hirano

Yanagimoto

et al. 2019

Neurology & Clinical Neurosc

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“…CYP27 is a member of the larger cytochrome P450 family and two functional domains, the adrenodoxin-binding site (residues 384-395) and the heme-binding site (residues 468-497), have been identified (14)(15)(16)55). In vitro transfection studies of mutant cDNAs that carry the Arg446Cys mutation (heme-binding domain) in COS cells showed low or undetectable levels of CYP27 enzyme activity (13,19). Structural mapping, using computer modeling, of the mutated missense amino acid residues in threedimensional structure of CYP27 allowed for prediction of the effects of these mutations on function.…”

Section: Discussionmentioning

confidence: 99%

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees

Lee

Hazard

Carpten

et al. 2001

Journal of Lipid Research

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Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disorder of bile acid biosynthesis. Clinically, CTX patients present with tendon xanthomas, juvenile cataracts, and progressive neurological dysfunction and can be diagnosed by the detection of elevated plasma cholestanol levels. CTX is caused by mutations affecting the sterol 27-hydroxylase gene ( CYP27 ). CTX has been identified in a number of populations, but seems to have a higher prevalence in the Japanese, Sephardic Jewish, and Italian populations. We have assembled 12 previously unreported pedigrees from the United States. The CYP27 locus had been previously mapped to chromosome 2q33-qter. We performed linkage analyses and found no evidence of genetic heterogeneity. All CTX patients showed segregation with the CYP27 locus, and haplotype analysis and recombinant events allowed us to precisely map CYP27 to chromosome 2q35, between markers D2S1371 and D2S424. Twenty-three mutations were identified from 13 probands analyzed thus far; 11 were compound heterozygotes and 2 had homozygous mutations. Of these, five are novel mutations [Trp100Stop, Pro408Ser, Gln428Stop, a 10-base pair (bp) deletion in exon 1, and a 2-bp deletion in exon 6 of the CYP27 gene]. Three-dimensional structural modeling of sterol 27-hydroxylase showed that, while the majority of the missense mutations disrupt the heme-binding and adrenodoxin-binding domains critical for enzyme activity, two missense mutations (Arg94Trp/Gln and Lys226Arg) are clearly located outside these sites and may identify a potential substrate-binding or other protein contact site.

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“…To determine the effect of the G to A mutation on the sterol 27-hydroxylase activity, 20 g plasmids carrying normal cDNA or mutant cDNA were transfected in triplicate into 1 ϫ 10 6 cells, as described above. After 48 h, cells were harvested and the mitochondrial fraction was prepared, as described (5). The isolated mitochondrial fraction was used for sterol 27-hydroxylase assay.…”

Section: Transfection Analysismentioning

confidence: 99%

“…Mutations in the sterol 27-hydroxylase gene ( CYP 27) cause cerebrotendinous xanthomatosis (CTX), an autosomal recessively inherited cholesterol metabolic disorder characterized by tendon xanthomatosis, cataracts, neurological manifestations, osteoporosis, and premature atherosclerosis. Since the cloning of human sterol 27-hydroxylase cDNA (2) and determination of its genomic structure (3), several mutations of the sterol 27-hydroxylase gene have been identified in CTX patients from different countries (4)(5)(6)(7)(8)(9)(10)(11)(12). Most of the mutations reported to date are point mutations that lead to amino acid substitution or premature termination codon.…”

mentioning

confidence: 99%

Alternative pre-mRNA splicing of the sterol 27-hydroxylase gene (CYP 27) caused by a G to A mutation at the last nucleotide of exon 6 in a patient with cerebrotendinous xanthomatosis (CTX)

Chen

Kubota

Seyama

1998

Journal of Lipid Research

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A recently identified G to A mutation at the last nucleotide of exon 6 of the sterol 27-hydroxylase gene ( CYP 27) in a patient with cerebrotendinous xanthomatosis (CTX) was shown here to cause alternative pre-mRNA splicing of the gene. Northern blot analysis of the patient's RNA revealed a broadened band in the human CYP 27 mRNA region compared to that of the normal sample, indicating that there may exist differently spliced mRNA species in the patient. RT-PCR produced three fragments in the patient, one was full-length size and the other two were of smaller sizes. Sequence analysis confirmed that the nucleotide of the full-length size was identical to that of the normal full-length cDNA, except for the G to A mutation at codon 362, which corresponds to the last nucleotide of exon 6. One of the smaller size species lacked exon 6 and the other was absent from the 3 Ј terminal 88 bp of exon 6 due to the use of an activated cryptic 5 Ј splice site in exon 6. The correctly spliced mRNA harbouring the G to A mutation was responsible for the deficiency of the sterol 27hydroxylase activity, as confirmed by transfection experiment. Transfection of constructed minigenes, with or without the mutation, showed that correctly spliced mRNA was observed in the normal minigene while the mutant minigene was differently spliced. This is the first report of a G to A substitution at the last nucleotide of an exon resulting in both normal and abnormal pre-mRNA splicings, including exon skipping and activating of a coding region cryptic 5 Ј splice site. The results reveal a new molecular basis for the CTX and provide information on aberrant splicing of pre-mRNA in multi-exon genes. -Chen, W., S. Kubota, and Y. Seyama. Alternative pre-mRNA splicing of the sterol 27-hydroxylase gene ( CYP 27) caused by a G to A mutation at the last nucleotide of exon 6 in a patient with cerebrotendinous xanthomatosis (CTX).

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Identification of new mutations in sterol 27-hydroxylase gene in Japanese patients with cerebrotendinous xanthomatosis (CTX).

Cited by 61 publications

References 21 publications

Neurologic findings are the sole manifestations of a patient with cerebrotendinous xanthomatosis

Neurologic findings are the sole manifestations of a patient with cerebrotendinous xanthomatosis

Fine-mapping, mutation analyses, and structural mapping of cerebrotendinous xanthomatosis in U.S. pedigrees

Alternative pre-mRNA splicing of the sterol 27-hydroxylase gene (CYP 27) caused by a G to A mutation at the last nucleotide of exon 6 in a patient with cerebrotendinous xanthomatosis (CTX)

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