| Autor: |
Nakamura, Akie, Hamaguchi, Erika, Horikawa, Reiko, Nishimura, Yasuyuki, Matsubara, Keiko, Sano, Shinichiro, Nagasaki, Keisuke, Matsubara, Yoichi, Umezawa, Akihiro, Tajima, Toshihiro, Ogata, Tsutomu, Kagami, Masayo, Okamura, Kohji, Fukami, Maki |
| Zdroj: |
The Journal of Clinical Endocrinology & Metabolism; July 2016, Vol. 101 Issue: 7 p2623-2627, 5p |
| Abstrakt: |
Context:Pseudohypoparathyroidism type 1b (PHP-1b) results from methylation defects at the G protein stimulatory α subunit (GNAS) exon A/B-differentially methylated region (DMR). Although microduplications in the GNASregion were recently identified in two PHP-1b patients, genetic information on these patients remained fragmentary.Case Description:A 20-year-old Japanese male and his mother presented with hypocalcemia and elevated blood levels of intact PTH. The proband had a maternal uncle who was previously diagnosed with PHP-1b. Methylation-specific multiplex ligation-dependent probe amplification, array-based comparative genomic hybridization, pyrosequencing, fluorescence in situ hybridization, and whole-genome sequencing were performed for this family. The proband, mother, and uncle carried maternally derived approximately 133-kb duplication-triplication-duplication rearrangements at 20q13.32 involving NESP55, NESPAS, XLαs, and exon A/B-DMR but not STX16or the Gsα coding region. These individuals exhibited partial methylation defects of NESP55-, NESPAS-, and XLαs-DMRs, which were ascribable to the increased copy numbers of these regions retaining the maternally derived methylation pattern and loss of methylation of exon A/B-DMR, which was inexplicable by the copy-number alterations. Fusion junctions of the rearrangement resided within non-repeat sequences and were accompanied by short-templated insertions.Conclusions:Our results indicate that maternally derived copy-number gains in the GNASregion mediated by nonhomologous end-joining and/or by break-induced replication can underlie autosomal dominant PHP-1b. These rearrangements likely affect methylation of exon A/B-DMR by disconnecting or disrupting its cis-acting regulator(s). This study provides a novel example of human disorders resulting from functional disturbance in the cis-regulatory machinery of DNA methylation. |
| Databáze: |
Supplemental Index |
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