vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ20.684vavilov-2846Research ArticleГЕНЕТИКА ЧЕЛОВЕКАHUMAN GENETICSСкрининг мутаций гена CYP1B1 у пациентов Западной Сибири с первичной врожденной глаукомойScreening of West Siberian patients with primary congenital glaucoma for CYP1B1 gene mutationshttps://orcid.org/0000-0002-0403-545XИванощукД. Е.IvanoshchukD. E.dinara2084@mail.ruhttps://orcid.org/0000-0002-0897-5473МихайловаС. В.MikhailovaS. V.https://orcid.org/0000-0001-8048-943XФеньковаО. Г.FenkovaO. G.https://orcid.org/0000-0001-6108-1025ШахтшнейдерЕ. В.ShakhtshneiderE. V.https://orcid.org/0000-0001-6311-5452ФурсоваА. Ж.FursovaA. Z.БычковИ. Ю.BychkovI. V.https://orcid.org/0000-0001-9425-413XВоеводаМ. И.VoevodaM. I.Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of Siberian Branch of the Russian Academy of SciencesRussian FederationГосударственная Новосибирская областная клиническая больницаРоссияNovosibirsk State Regional HospitalRussian FederationНовосибирский филиал ФГАУ НМИЦ «МНТК Микрохирургия глаза» им. академика С.Н. ФедороваРоссияS.N. Fyodorov FSBI IRTC Eye Microsurgery, Novosibirsk branchRussian Federation202031122020248861867Copyright © Иванощук Д.Е., Михайлова С.В., Фенькова О.Г., Шахтшнейдер Е.В., Фурсова А.Ж., Бычков И.Ю., Воевода М.И., 20202020Иванощук Д.Е., Михайлова С.В., Фенькова О.Г., Шахтшнейдер Е.В., Фурсова А.Ж., Бычков И.Ю., Воевода М.И.Ivanoshchuk D.E., Mikhailova S.V., Fenkova O.G., Shakhtshneider E.V., Fursova A.Z., Bychkov I.V., Voevoda M.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2846

Первичная врожденная глаукома – это патология органа зрения, которая приводит к прогрессирующей слепоте и слабовидению у детей. Основной ее причиной являются аномалии/нарушения развития угла передней камеры глаза. Большинство случаев возникновения первичной врожденной глаукомы спорадические, но описаны и семейные варианты с аутосомно-рецессивным (преимущественно) и аутосомнодоминантным (редко) типом наследования. Врожденная глаукома – редкое заболевание (один случай на 10 000–20 000 новорожденных), но частота ее возникновения существенно возрастает (до одного случая на 250 новорожденных) в странах, где распространены близкородственные браки. Мутации в гене CYP1B1, который кодирует цитохром P450 1B1, становятся наиболее частой причиной аутосомно-рецессивных форм первичной врожденной глаукомы. Известно, что этот фермент участвует в метаболизме ретиноевой кислоты и необходим для нормального развития глаза. Целью нашей работы была оценка полиморфизма гена CYP1B1 у пациентов Западной Сибири с первичной врожденной глаукомой. Было проведено прямое автоматическое секвенирование по Сэнгеру экзонов и прилегающих сайтов сплайсинга гена CYP1B1 у 28 человек из Западно-Сибирского региона с фенотипом первичной врожденной глаукомы. В результате в обследованной нами выборке европеоидного населения выявлены ранее описанные в других этнических группах патогенные варианты этого гена: E387K (rs55989760), R444 * (rs377049098), R444Q (rs72549376) и P437L (rs56175199), а также новая однонуклеотидная делеция, приводящая к сдвигу рамки считывания p.F114Lfs*38 в гене CYP1B1. Последняя может вызывать образование белка с измененным аминокислотным составом и укороченного белка. Ни одна из выявленных мутаций не была выявлена в контрольной выборке офтальмологически обследованных лиц без первичной врожденной глаукомы (100 человек). Варианты R444* (rs377049098) и R444Q (rs72549376) не были найдены также в популяционной выборке (576 лиц, отобранных случайным образом) жителей Западной Сибири. Все обнаруженные варианты вызывали развитие аутосомно-рецессивной формы первичной врожденной глаукомы. При этом наиболее тяжелая клиника наблюдалась у носителей мутаций в 444 кодоне гена. Следовательно, у детей с признаками повышения внутриглазного давления оправдано проведение молекулярно-генетического анализа гена CYP1B1 для ранней диагностики и своевременного начала терапии первичной врожденной глаукомы.

Primary congenital glaucoma (PСG) is a visual organ pathology that leads to progressive blindness and poor vision in children. Its main cause is an anomaly of the anterior chamber angle. Most cases of PСG are sporadic, but familial cases with an autosomal recessive (predominantly) and autosomal dominant (rare) type of inheritance have been described. Congenital glaucoma is a rare condition (1 case per 10,000–20,000 newborns), but its prevalence is substantially higher (up to 1 case per 250 newborns) in countries where consanguineous marriages are common. Mutations in the CYP1B1 gene, which encodes cytochrome P450 1B1, are the most common cause of autosomal recessive primary congenital glaucoma. This enzyme is known to be involved in retinoic acid metabolism and is necessary for normal eye development. The aim of this work was to assess the polymorphism of the CYP1B1 gene among West Siberian patients with primary congenital glaucoma. Direct automatic Sanger sequencing of exons and adjacent splicing sites of the CYP1B1 gene was carried out in 28 people with the PCG phenotype from a West Siberian region. As a result, in the sample of the white population we examined, pathogenic variants previously described in other ethnic groups were revealed: E387K (rs55989760), R444* (rs377049098), R444Q (rs72549376), and P437L (rs56175199), as well as novel single-nucleotide deletion p.F114Lfs*38 in the CYP1B1 gene. The latter can cause a frame shift, changed amino acid composition, and a formation of truncated in the protein. None of the detected mutations were found in the control sample of ophthalmologically examined individuals without PCG (100 people). Variants R444* (rs377049098) and R444Q (rs72549376) were not found in the general population sample either (576 randomly selected West Siberia residents). All the detected mutations caused the development of the autosomal recessive form of primary congenital glaucoma. The most severe clinical phenotype was observed in carriers of mutations in codon 444 of the gene. Consequently, in children with signs of increased intraocular pressure, molecular genetic analysis of the CYP1B1 gene is advisable for early diagnosis and timely initiation of PCG therapy.

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The authors declare that there are no conflicts of interest present.