Синдром Смит-Магенис. В помощь родителям

Ресурсы и литература

Французская ассоциация Смит—Магенис (Association of Smith-Magenis France)

association@smithmagenis.com

Справочная по генетике Национальной медицинской библиотеки

(National Library of Medicine Genetics Home Reference)

ghr.nlm.nih.gov

PRISMS: Родители и ученые, интересующиеся синдромом Смит—Магенис

Parents and Researchers Interested in Smith-Magenis Syndrome (PRISMS)
info@prisms.org

www.prisms.org

Фонд синдрома Смит—Магенис

Smith-Magenis Syndrome Foundation
info@smith-magenis.co.uk

www.smith-magenis.co.uk

 Регистр исследований и банк тканей СМС Национального института здоровья

National Institutes of Health (NIH) SMS Research Registry and Tissue Bank (USA)
acmsmith@mail.nih.gov

clinicaltrials.gov

Молекулярная генетика

Таблица А. Синдром Смит—Магенис: гены и базы данных
Ген Локус Белок База данных LOVD

База данных HGMD
RAI1
 17p11.2 Белок1, индуцированный ретиноевой кислотой (retinoic acid-induced protein1) databases.lovd.nl hgmd.cf.ac.uk
  Название гена: http://www.ncbi.nlm.nih.gov/gene/10743 Локализация: http://www.ncbi.nlm.nih.gov/projects/mapview/maps.cgi?taxid=9606&chr=17&query=RAI1&qstr=RAI1&maps=snp,genes-r,pheno&zoom=2 Название белка: http://www.uniprot.org/uniprot/Q7Z5J4   Таблица Б. Синдром Смит—Магенис в OMIM (база данных «Менделевское наследование у человека») 
182290 SMITH-MAGENIS SYNDROME; SMS http://omim.org/entry/182290
607642 RETINOIC ACID-INDUCED GENE 1; RAI1 http://omim.org/entry/607642

Патогенез

Синдром Смит—Магенис относится к синдромам, вызванным делецией группы соседних генов. У 70% больных делеция заключается в выпадении около 3,5 млн нуклеотидов (Potocki et al 2003, Vlangos et al 2003). За развитие СМС ответственен участок хромосомы длиной менее 650000 нуклеотидов, находящийся в сегменте 17p11.2 (Schoumans et al 2005, Vlangos et al 2005). Мутации гена RAI1 тоже приводят к развитию СМС (см.табл.3). Нормальные аллельные варианты. Ген имеет шесть экзонов. Мутантные аллельные варианты. У людей с фенотипическими проявлениями СМС, не имеющих обнаруживаемой делеции 17p11.2, выявлены доминантные мутации гена RAI1 (Slager et al 2003, Bi et al 2004, Girirajan et al 2005, Truong et al 2010). См.табл.3. Таблица 3. Некоторые мутантные аллельные варианты генаRAI1 
Последовательность нуклеотидов Замена аминокислоты*

Секвенирование
c.253_271del19 p.Leu85CysfsX55 NM_030665.3 www.ncbi.nlm.nih.gov       NP_109590.3 www.ncbi.nlm.nih.gov  
c.1119delC p.Gln374SerfsX65
c.1449delC p.Glu484LysfsX35
c.2773_2801del29 p.Val1925ArgfsX9
c.2878C>T p.Arg960X
c.3103delC p.Gln1035ArgfsX29
c.3103dupC p.Gln1035ProfsX31
c.3801delC p.Thr1268ProfsX47
c.4649delC p.Ser1550PhefsX37
c.4685A>G p.Gln1562Arg
c.4933_4936del p.Ala1645GlyfsX35
c.5423G>A p.Ser1808Asn
c.5265delC p.Arg1756GlyfsX94
Ссылки на мутантные аллельные варианты: Slager et al (2003), Bi et al (2004), Girirajan et al (2005), Girirajan et al (2006), Truong et al (2010). * Номенклатура мутаций со сдвигом рамки считывания: замена аминокислоты в месте сдвига рамки считывания (fs— frame shift), за которым следует обозначение кодона, на котором заканчивается новая рамка считывания, с указанием его положения (Х#). Место окончания трансляции в новой рамке считывания высчитывают начиная с первой замененной аминокислоты, появившейся из-за сдвига рамки, и заканчивая первым терминирующим кодоном (Х#). (См. www.hgvs.org). Продукт нормального гена. Полагают, что белок1, индуцированный ретиноевой кислотой, является регулятором транскрипции (Bi et al 2004, Burns et al 2010, Carmona-Mora et al 2010); однако для более полной оценки его функций в клетке нужны дополнительные исследования. Продукт мутантного гена. Неизвестно, как мутации генаRAI1 изменяют функцию кодируемого им белка. Поскольку причиной фенотипических проявлений СМС, по-видимому, служит гаплонедостаточность, полагают, что мутации генаRAI1 приводят к образованию нефункционирующего белка1, индуцированного ретиноевой кислотой.

Литература

Для поиска литературы по медицинской генетике можно воспользоваться специальной формой для клиницистов в базе данных PubMed: http://www.ncbi.nlm.nih.gov/pubmed/clinical. 

Цитируемая литература

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Рекомендуемая литература

  1. Elsea SH, Girirajan S. Smith-Magenis syndrome. Eur J Hum Genet. 2008;16:412–21. [PubMed]
  2. Elsea SH, Williams SR. Smith-Magenis syndrome: haploinsufficiency of RAI1 results in altered gene regulation in neurological and metabolic pathways. Expert Rev Mol Med. 2011;13:e14. [PubMed]
  3. Williams SR, Girirajan S, Tegay D, Nowak NJ, Hatchwell E, Elsea SH. Array comparative genomic hybridization of 52 subjects with a Smith-Magenis-like phenotype: identification of dosage-sensitive loci also associated with schizophrenia, autism, and developmental delay. J Med Genet. 2009;47:223–9. [PubMed]