Identification of ABCC6 gene mutations in the Japanese patients with pseudoxanthoma elasticum (PXE)

Purpose. To report the spectrum of ABCC6 variants in Japanese patients with angioid streaks (AS). Patients and Methods. This was a single-center cohort study. The medical records of 20 patients with AS from 18 unrelated Japanese families were retrospectively reviewed. Screening of the ABCC6 gene (exons 1 to 31) was performed using PCR-based Sanger sequencing. Results. Eight ABCC6 variants were identified as candidate disease-causing variants. These eight variants included five known variants (p.Q378X, p.R419Q, p.V848CfsX83, p.R1114C, and p.R1357W), one previously reported variant (p.N428S) of unknown significance, and two novel variants (c.1939C>T [p.H647Y] and c.3374C>T [p.S1125F]); the three latter variants were determined to be variants of significance. The following four variants were frequently identified: p.V848CfsX83 (14/40 alleles, 35.0%), p.Q378X (7/40 alleles, 17.5%), p.R1357W (6/40 alleles, 15.0%), and p.R419Q (4/40 alleles, 10.0%). The ABCC6 variants were identified in compound heterozygous or homozygous states in 13 of 18 probands. Two families showed a pseudodominant inheritance pattern. Pseudoxanthoma elasticum was seen in 15 of 17 patients (88.2%) who underwent dermatological examination. Conclusions. We identified disease-causing ABCC6 variants that were in homozygous or compound heterozygous states in 13 of 18 families (72.2%). Our results indicated that ABCC6 variants play a significant role in patients with AS in the Japanese population.

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New ABCC6 gene mutations in German pseudoxanthoma elasticum patients

Journal of Molecular Medicine ◽

10.1007/s00109-004-0588-2 ◽

2004 ◽

Vol 83 (2) ◽

pp. 140-147 ◽

Cited By ~ 21

Author(s):

Doris Hendig ◽

Veronika Schulz ◽

Jutta Eichgr�n ◽

Christiane Szliska ◽

Christian G�tting ◽

...

Keyword(s):

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Abcc6 Gene

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Role of Serum Fetuin-A, a Major Inhibitor of Systemic Calcification, in Pseudoxanthoma Elasticum

Clinical Chemistry ◽

10.1373/clinchem.2005.059253 ◽

2006 ◽

Vol 52 (2) ◽

pp. 227-234 ◽

Cited By ~ 60

Author(s):

Doris Hendig ◽

Veronika Schulz ◽

Marius Arndt ◽

Christiane Szliska ◽

Knut Kleesiek ◽

...

Keyword(s):

Blood Donors ◽

Family Members ◽

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Elastic Fibers ◽

Fetuin A ◽

Cardiovascular Involvement ◽

Abcc6 Gene ◽

Sandwich Enzyme Immunoassay

Abstract Background: Pseudoxanthoma elasticum (PXE) is a hereditary disorder of the connective tissue affecting the skin, retina, and cardiovascular system and characterized by progressive calcification of abnormal and fragmented elastic fibers in the extracellular matrix. The aim of the present study was to investigate the association of fetuin-A, a major systemic inhibitor of calcification, with PXE. Methods: Fetuin-A was measured by quantitative sandwich enzyme immunoassay in sera from 110 German patients with PXE, 53 unaffected first-degree family members, and 80 healthy blood donors. We determined the distribution of the fetuin-A polymorphisms c.742C>T (p.T248M) and c.766C>G (p.T256S) in these same 3 groups. The occurrences of the frequent ABCC6 gene mutations c.3421C>T (p.R1141X) and c.EX23_EX29del were also assessed. Results: Serum fetuin-A concentrations in male and female PXE patients were lower than in unaffected first-degree relatives and controls [mean (SD) concentrations, 0.55 (0.11) g/L in patients; 0.70 (0.23) g/L in relatives; and 0.80 (0.23) g/L in controls (P <0.0001)]. Serum fetuin-A was higher in female PXE patients with cardiovascular involvement than in the corresponding male group (P <0.05). The fetuin-A polymorphism frequencies did not differ among PXE patients, family members, and blood donors. Conclusion: A deficiency of multidrug resistance-associated protein 6 leads to alteration of circulating substrates, e.g., inhibitors of calcification as fetuin-A, leading to progressive mineralization of elastic fibers in PXE.

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Pseudoxanthoma Elasticum, Kidney Stones and Pyrophosphate: From a Rare Disease to Urolithiasis and Vascular Calcifications

International Journal of Molecular Sciences ◽

10.3390/ijms20246353 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6353 ◽

Cited By ~ 4

Author(s):

Emmanuel Letavernier ◽

Elise Bouderlique ◽

Jeremy Zaworski ◽

Ludovic Martin ◽

Michel Daudon

Keyword(s):

Rare Disease ◽

Kidney Stones ◽

Genetic Disorders ◽

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Elastic Fibers ◽

Mendelian Disease ◽

Vascular Calcifications ◽

Stone Formers ◽

Abcc6 Gene

Pseudoxanthoma elasticum is a rare disease mainly due to ABCC6 gene mutations and characterized by ectopic biomineralization and fragmentation of elastic fibers resulting in skin, cardiovascular and retinal calcifications. It has been recently described that pyrophosphate (a calcification inhibitor) deficiency could be the main cause of ectopic calcifications in this disease and in other genetic disorders associated to mutations of ENPP1 or CD73. Patients affected by Pseudoxanthoma Elasticum seem also prone to develop kidney stones originating from papillary calcifications named Randall’s plaque, and to a lesser extent may be affected by nephrocalcinosis. In this narrative review, we summarize some recent discoveries relative to the pathophysiology of this mendelian disease responsible for both cardiovascular and renal papillary calcifications, and we discuss the potential implications of pyrophosphate deficiency as a promoter of vascular calcifications in kidney stone formers and in patients affected by chronic kidney disease.

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Clinical Phenotypes and ABCC6 Gene Mutations in Brazilian Families with Pseudoxanthoma Elasticum

Acta Dermato Venereologica ◽

10.2340/00015555-1570 ◽

2013 ◽

Vol 93 (6) ◽

pp. 739-740 ◽

Cited By ~ 1

Author(s):

C Faria ◽

Q Li ◽

H Guo ◽

J Uitto ◽

S Takeno ◽

...

Keyword(s):

Gene Mutations ◽

Pseudoxanthoma Elasticum ◽

Clinical Phenotypes ◽

Abcc6 Gene

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Novel mutations of ABCC6 gene in Japanese patients with Angioid streaks

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2009.01.117 ◽

2009 ◽

Vol 380 (3) ◽

pp. 548-553 ◽

Cited By ~ 14

Author(s):

Naoyuki Sato ◽

Tomohiro Nakayama ◽

Yoshihiro Mizutani ◽

Mitsuko Yuzawa

Keyword(s):

Japanese Patients ◽

Angioid Streaks ◽

Novel Mutations ◽

Abcc6 Gene

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2P-0448 Two prevalent mutations in the ATP-binding cassette transporters ABCC6 Japanese patients with pseudoxanthoma elasticum (PXE)

Atherosclerosis Supplements ◽

10.1016/s1567-5688(03)90590-3 ◽

2003 ◽

Vol 4 (2) ◽

pp. 138

Author(s):

Y. Noji ◽

A. Inazu ◽

T. Higashikata ◽

M. Kawashiri ◽

S. Katsuda ◽

...

Keyword(s):

Pseudoxanthoma Elasticum ◽

Japanese Patients ◽

Atp Binding ◽

Atp Binding Cassette Transporters ◽

Atp Binding Cassette

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Frequency of homologous recombination associated gene mutations in Japanese patients with ovarian cancer

Gynecologic Oncology ◽

10.1016/s0090-8258(21)00953-7 ◽

2021 ◽

Vol 162 ◽

pp. S163-S164

Author(s):

Kosuke Yoshihara ◽

Tsukasa Baba ◽

Mueaki Shimada ◽

Hiroshi Yoshida ◽

Aikou Okamoto ◽

...

Keyword(s):

Ovarian Cancer ◽

Homologous Recombination ◽

Gene Mutations ◽

Japanese Patients

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Mice Carrying a Schizophrenia-associated Mutation of the Arhgap10 Gene Are Vulnerable to the Effects of Methamphetamine Treatment on Cognitive Function: Association With Morphological Abnormalities in Striatal Neurons

10.21203/rs.3.rs-94489/v1 ◽

2020 ◽

Author(s):

Kazuhiro Hada ◽

Bolati Wulaer ◽

Taku Nagai ◽

Norimichi Itoh ◽

Masahito Sawahata ◽

...

Keyword(s):

Rho Gtpase ◽

Genetic Model ◽

Gene Mutations ◽

Missense Variant ◽

Japanese Patients ◽

Copy Number Variations ◽

Spine Density ◽

Striatal Neurons ◽

Expression Levels ◽

Significant Impairment

Abstract We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele, because two mutations in the same gene are considered a typical genetic model of severe schizophrenia. Accordingly, we generated a mouse model (ARHGAP10NHEJ/S490P mice) carrying a missense variant and a coexisting frameshift mutation (NHEJ). We examined the spatiotemporal expression of Arhgap10 mRNA in the brain and found the highest expression levels in the striatum and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in ARHGAP10NHEJ/S490P mice compared with WT littermates. ARHGAP10NHEJ/S490P mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination (VD) learning between ARHGAP10NHEJ/S490P and WT mice, but a significant impairment of VD was evident in ARHGAP10NHEJ/S490P mice but not WT mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of ARHGAP10NHEJ/S490P mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality in the striatum and NAc neurons, which may be associated with vulnerability of cognition to methamphetamine treatment.

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