<i>POR</i> R457H is a global founder mutation causing Antley–Bixler syndrome with autosomal recessive trait

Adachi, Masanori; Asakura, Yumi; Matsuo, Mari; Yamamoto, Toshiyuki; Hanaki, Keiichi; Arlt, Wiebke

doi:10.1002/ajmg.a.31112

Cited by 29 publications

(24 citation statements)

References 12 publications

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“…92,93 The most frequent mutation in Caucasians is p.A287P, 92 while p.R457H is the most frequent mutation in Japanese populations. 94,95 In one study of 30 patients with POR deficiency from 11 countries, 23 POR mutations including a deletion and a partial duplication were detected by MLPA, and only 22% of unrelated patients carried homozygous POR mutations. 91 POR deficiency may present as a form of apparent 17,20 lyase deficiency due to mutations in the POR gene rather than the CYP17A1 gene.…”

Section: P450 Oxidoreductase Deficiencymentioning

confidence: 99%

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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Section: P450 Oxidoreductase Deficiencymentioning

confidence: 99%

Genetics of Congenital Adrenal Hyperplasia

Hannah‐Shmouni

Chen²,

Merke

2017

Endocrinology and Metabolism Clinics of North America

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“…Our long-standing biochemical research into the mechanism of this critical flavoprotein (12) led us to explore the structure/ function relationships responsible for these phenotypes by expressing and purifying POR variants of interest reported in the literature (13)(14)(15)(16)(17)(18)(19)(20). The variant A287P was reported as the most common mutation found in the Caucasian population (10,14), and these studies were verified and extended to establish genotype-phenotype correlations in a cohort of patients from 11 countries (21).…”

mentioning

confidence: 99%

Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype

McCammon

Panda

Xia

et al. 2016

Journal of Biological Chemistry

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Human NADPH-cytochrome P450 oxidoreductase (POR) gene mutations are associated with severe skeletal deformities and disordered steroidogenesis. The human POR mutation A287P presents with disordered sexual development and skeletal malformations. Difficult recombinant expression and purification of this POR mutant suggested that the protein was less stable than WT. The activities of cytochrome P450 17A1, 19A1, and 21A2, critical in steroidogenesis, were similar using our purified, full-length, unmodified A287P or WT POR, as were those of several xenobiotic-metabolizing cytochromes P450, indicating that the A287P protein is functionally competent in vitro, despite its functionally deficient phenotypic behavior in vivo. Differential scanning calorimetry and limited trypsinolysis studies revealed a relatively unstable A287P compared with WT protein, leading to the hypothesis that the syndrome observed in vivo results from altered POR protein stability. The crystal structures of the soluble domains of WT and A287P reveal only subtle differences between them, but these differences are consistent with the differential scanning calorimetry results as well as the differential susceptibility of A287P and WT observed with trypsinolysis. The relative in vivo stabilities of WT and A287P proteins were also examined in an osteoblast cell line by treatment with cycloheximide, a protein synthesis inhibitor, showing that the level of A287P protein post-inhibition is lower than WT and suggesting that A287P may be degraded at a higher rate. Current studies demonstrate that, unlike previously described mutations, A287P causes POR deficiency disorder due to conformational instability leading to proteolytic susceptibility in vivo, rather than through an inherent flavin-binding defect.

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“…Our patient was a compound heterozygote of c.1329_1330insC (I444fsX449) and c.1370G>A (R457H), both of which have previously been reported to be pathologic mutations [1,2]. A single basepair insertion between c.1329 and c.1330 leads to a frameshift, resulting in premature termination of translation (I444fsX449).…”

Section: Discussionmentioning

confidence: 83%

“…3). The former was first described in a Japanese patient, and the latter is the most frequently found POR mutation in Japanese ABS patients [1,2].…”

Section: Case Reportmentioning

confidence: 94%

A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene

Cheon

Kim

et al. 2008

Eur J Pediatr

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Antley-Bixler syndrome (ABS) is a skeletal malformation syndrome primarily affecting the skull and limbs. Although causal mutations in the FGFR2 gene have been found in some patients, mutations in the electron donor enzyme P450 oxidoreductase gene (POR) have recently been found to cause ABS in other patients. In addition to skeletal malformations, POR deficiency also causes glucocorticoid deficiency and congenital adrenal hyperplasia with ambiguous genitalia in both sexes. Here, we report on a 7-month-old Korean girl with ABS and ambiguous genitalia who was confirmed by POR gene analysis. Our patient showed typical skeletal findings with brachycephaly, mid-face hypoplasia, and radiohumeral synostosis. She also had partial labial fusion and a single urogenital orifice, as well as increased 17α-hydroxyprogesterone levels, suggesting a 21-hydroxylase deficiency. Cortisol and DHEA-sulfate response to rapid adrenocorticotropic hormone (ACTH) stimulation was inadequate. Direct sequencing of the POR gene revealed compound heterozygous mutations (I444fsX449 and R457H). This is the first report of a Korean patient with ABS caused by POR gene mutations.

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POR R457H is a global founder mutation causing Antley–Bixler syndrome with autosomal recessive trait

Cited by 29 publications

References 12 publications

Genetics of Congenital Adrenal Hyperplasia

Genetics of Congenital Adrenal Hyperplasia

Instability of the Human Cytochrome P450 Reductase A287P Variant Is the Major Contributor to Its Antley-Bixler Syndrome-like Phenotype

A case of Antley-Bixler syndrome caused by compound heterozygous mutations of the cytochrome P450 oxidoreductase gene

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