Neuromuscular DiseasesNeuromuscular DiseasesНервно-мышечные болезни2222-87212413-0443Publishing House ABV Press49810.17650/2222-8721-2022-12-3-36-44ORIGINAL REPORTSОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯCharacteristics of genetic changes in the SMN1 gene in spinal muscular atrophy 5qИсследование особенностей генетических изменений гена SMN1 при спинальной мышечной атрофии 5qhttps://orcid.org/0000-0002-3708-3378DilA. V.ДильА. В.
Russian Federation

Alena Vladimirovna Dil

41 Kirochnaya St., Saint-Petersburg 191015

Алена Владимировна Диль

191015 Санкт-Петербург, ул. Кирочная, 41

dil-alena@mail.ruhttps://orcid.org/0000-0002-9354-8790NazarovV. D.НазаровВ. Д.
Russian Federation

6–8 Lva Tolstogo St., Saint-Petersburg 197022

197022 Санкт-Петербург, ул. Льва Толстого, 6–8

https://orcid.org/0000-0001-8503-0759SidorenkoD. V.СидоренкоД. В.
Russian Federation

6–8 Lva Tolstogo St., Saint-Petersburg 197022

197022 Санкт-Петербург, ул. Льва Толстого, 6–8

https://orcid.org/0000-0002-4998-3699LapinS. V.ЛапинС. В.
Russian Federation

6–8 Lva Tolstogo St., Saint-Petersburg 197022

197022 Санкт-Петербург, ул. Льва Толстого, 6–8

https://orcid.org/0000-0002-2079-0439EmanuelV. L.ЭмануэльВ. Л.
Russian Federation

6–8 Lva Tolstogo St., Saint-Petersburg 197022

197022 Санкт-Петербург, ул. Льва Толстого, 6–8

I.I. Mechnikov North-Western State Medical University, Ministry of Health of RussiaФГБОУ ВО «Северо-Западный государственный медицинский университет им. И.И. Мечникова» Минздрава РоссииI.P. Pavlov First Saint Petersburg State Medical University, Ministry of Health of RussiaФГБОУ ВО «Первый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России2109202212336442109202221092022Copyright ©; 2022, Dil A.V., Nazarov V.D., Sidorenko D.V., Lapin S.V., Emanuel V.L.Copyright ©; 2022, Диль А.В., Назаров В.Д., Сидоренко Д.В., Лапин С.В., Эмануэль В.Л.2022Dil A.V., Nazarov V.D., Sidorenko D.V., Lapin S.V., Emanuel V.L.Диль А.В., Назаров В.Д., Сидоренко Д.В., Лапин С.В., Эмануэль В.Л.https://creativecommons.org/licenses/by/4.0https://nmb.abvpress.ru/jour/article/view/498

Background. Proximal spinal muscular atrophy 5q (5q‑SMA) is one of the most common neuromuscular diseases, which is caused by mutations of the SMN1 gene. Despite the fact that most studies consider SMN1 “deletion” as the most common cause of 5q‑SMA, gene loss is in fact associated with both classical deletions and conversions of SMN1 and SMN2, as well as with formation of chimeric structures. Up to now, far too little attention has been paid to the prevalence of types of SMN1 loss. However, different types of mutations can have different influence on the clinical findings and the effectiveness of therapy. A deeper study of the structure of these genes will allow us to determine the predictors of response to treatment and bring us closer to understanding the reasons for the instability of the SMN region.Aim. To study genetic changes in the SMN1 gene, as well as the number of copies of the SMN1 and SMN2 genes in 5q‑SMA.Materials and methods. The study involved 703 patients, for whom the analysis of the number of copies of SMN1 and SMN2 was performed in the center of molecular medicine of I.P. Pavlov First Saint Petersburg State Medical University for 2018–2021. Gene copy number analysis was performed by multiplex ligation‑dependent probe amplification (MLPA) using the SALSA MLPA P021 SMA kit (MRC Holland).Results. Among 703 participants, a homozygous SMN1 deletion was found in 167 (24 %), 76 (11 %) were carriers of the deletion and no aberrations were found in the remaining 460 (65 %). Among patients with a homozygous deletion, 41 (24 %) cases of a true deletion were identified. Also, 11 (7 %) cases of partial deletion with a homozygous loss of the 7th exon and heterozygous of the 8th exon of SMN1 were identified. The most common type of aberration was the conversion of SMN1 to SMN2 – 94 (56 %) cases, which is characterized by a homozygous loss of SMN1 and a reciprocal increase in SMN2 copies. In addition, 21 (13 %) cases of the formation of hybrid genes were found.Conclusion. Types of genetic aberrations in 5q‑SMA have not been studied enough yet. A search of the literature revealed very few studies which results are comparable with ours. However, further research of genetic changes in SMN1 and SMN2 might bring more clarity on the causes and mechanisms of this disease, and get us closer to finding the most effective method of treatment.

Введение. Проксимальная спинальная мышечная атрофия 5q (5q‑СМА) представляет собой одно из наиболее распространенных нервно‑мышечных заболеваний, в основе которого лежат аберрации гена SMN1. Несмотря на то, что в большинстве исследований говорят о «делеции» SMN1 как о самой распространенной причине 5q‑СМА, потеря гена связана как с классическими делециями, так и с конверсией SMN1 и SMN2, а также с образованием химерных структур. На сегодняшний день недостаточно данных о распространенности того или иного типа потери SMN1. Однако разные виды мутаций могут оказывать различное влияние на клиническую картину и эффективность терапии. Более глубокое изучение строения генов позволит определить предикторы ответа на терапию и приблизиться к пониманию причин нестабильности региона SMN.Цель исследования – изучить особенности генетических аберраций, а также количество копий генов SMN1 и SMN2 при 5q‑СМА.Материалы и методы. В исследовании приняло участие 703 пациента, для которых был проведен анализ количества копий SMN1 и SMN2 в Научно‑методическом центре Минздрава России по молекулярной медицине ФГБОУ ВО «Первый Санкт‑Петербургский государственный медицинский университет им. акад. И.П. Павлова» Минздрава России за 2018–2021 гг. Анализ числа копий генов проводился методом мультиплексной амплификации лигированных проб (MLPA) с использованием набора SALSA MLPA P021 SMA (MRC Holland) в соответствии с инструкцией производителя.Результаты. Среди 703 участников гомозиготная делеция SMN1 обнаружена у 167 (24 %), носительство делеции – у 76 (11 %), у оставшихся 460 (65 %) аберраций не выявлено. Среди пациентов с гомозиготной делецией выявлен 41 случай (24 %) истинной делеции. Также выявлены 11 (7 %) случаев частичной делеции с гомозиготной потерей 7‑го и гетерозиготной потерей 8‑го экзона SMN1. Наиболее распространенным типом аберраций являлась конверсия SMN1 в SMN2 (94 (56 %) случая), которая характеризуется гомозиготной потерей SMN1 и реципрокным увеличением числа копий SMN2. Кроме того, обнаружен 21 (13 %) случай формирования гибридных генов.Выводы. Генетические аберрации при 5q‑СМА на сегодняшний день изучены недостаточно. Тем не менее полученные нами результаты сопоставимы с имеющимися данными мировой литературы. Дальнейшее исследование особенностей изменений SMN1 и SMN2 позволит пролить свет на причины и механизмы развития данного заболевания, а также приблизиться к поиску наиболее эффективных точек приложения терапии.

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