Background. This study deals with a rare (orphan) monogenic connective tissue disorder - Ehlers-Danlos syndrome kyphoscoliotic type 2 (EDSKS2). Kyphoscoliotic type 2 Ehlers-Danlos syndrome is an autosomal recessive disorder caused by mutations in the FKBP14 gene (7p14.3), which encodes the FKBP22 protein. According to the 2017 classification, this type is in group seven - collagen spatial structure and cross-linking defects. We present results of clinical examination and molecular genetic analysis for five patients with age varying from two to fifteen years. Methods. Five patients were examined using clinical and laboratory methods. DNA samples used for the analysis were extracted from whole blood samples using a Wizard® Genomic DNA Purification Kit (Promega, USA) according to the manufacturer's protocol. Results. The major clinical findings were kyphoscoliosis, early motor development delay, muscular weakness, hypotonia and hearing loss. Molecular genetic analysis detected a homozygous c.362dupC duplication in exon 3 of the FKBP14 gene in all five patients. This mutation is common in various countries. Differential diagnostics were carried out to exclude other Ehlers-Danlos syndrome types and myopathies. Conclusions. Literature analysis and examination of five EDSKS2 patients demonstrated the involvement of major organs and systems, such as joints, spine, muscles, cardiovascular system, respiratory system, hearing, and vision, into the pathological process. Kidney mobility increases and nephroptosis seems to be secondary caused by muscular weakness. During molecular genetic analysis, to verify EDSKS2 it is recommended to initially search for the c.362dupC duplication, which appears to be common in European countries, including Russia.
Testicular microlithiasis (TM) is one of the symptoms of testicular dysgenesis syndrome (TDS). TM is particularly interesting as an informative marker of testicular germ cell tumors (TGCTs). KIT ligand gene (KITLG), BCL2 antagonist/killer 1 (BAK1), and sprouty RTK signaling antagonist 4 (SPRY4) genes are associated with a high risk of TGCTs, whereas bone morphogenetic protein 7 gene (BMP7), transforming growth factor beta receptor 3 gene (TGFBR3), and homeobox D cluster genes (HOXD) are related to TDS. Using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, we investigated allele and genotype frequencies for KITLG (rs995030, rs1508595), SPRY4 (rs4624820, rs6897876), BAK1 (rs210138), BMP7 (rs388286), TGFBR3 (rs12082710), and HOXD (rs17198432) in 142 TGCT patients, 137 TM patients, and 153 fertile men (control group). We found significant differences in the KITLG GG_rs995030 genotype in TM (P = 0.01) and TGCT patients (P = 0.0005) compared with the control. We also revealed strong associations between KITLG_rs1508595 and TM (G allele, P = 0.003; GG genotype, P = 0.01) and between KITLG_rs1508595 and TGCTs (G allele, P = 0.0001; GG genotype, P = 0.0007). Moreover, there was a significant difference in BMP7_rs388286 between the TGCT group and the control (T allele, P = 0.00004; TT genotype, P = 0.00006) and between the TM group and the control (T allele, P = 0.04). HOXD also demonstrated a strong association with TGCTs (rs17198432 A allele, P = 0.0001; AA genotype, P = 0.001). Furthermore, significant differences were found between the TGCT group and the control in the BAK1_rs210138 G allele (P = 0.03) and the GG genotype (P = 0.01). KITLG and BMP7 genes, associated with the development of TGCTs, may also be related to TM. In summary, the KITLG GG_rs995030, GG_rs1508595, BMP7 TT_rs388286, HOXD AA_rs17198432, and BAK1 GG_rs210138 genotypes were associated with a high risk of TGCT development.
Статья посвящена редкой патологии из группы болезней накопления с аутосомно-рецессивным типом наследования-муколипидозу II и IIIA типов. Заболевание отличается большим фенотипическим сходством с мукополисахаридозом. Цель работы: анализ генофенотипических показателей у российских больных с муколипидозом II и IIIA типов. Активность лизосомных ферментов в плазме (β-глюкуронидазы, общей гексозаминидазы и N-ацетил-альфа-D-глюкозаминидазы) измерялась по стандартной методике с использованием хромогенных и флюорогенных субстратов. Геномная ДНК лейкоцитов периферической крови выделялась с помощью набора реактивов Preb 100 (DIAtom TM). Амплификация всех экзонов гена GNPTAB проводилась методом полимеразной цепной реакции (ПЦР) с последующим прямым нерадиоактивным секвенированием по Сэнгеру. Обследованы 50 больных в возрасте от 1,5 до 10 лет. Клиническая симптоматика болезни включала: Гурлер-подобный фенотип, задержку роста, поражение скелета, сердца и сосудов, ЦНС. Муколипидоз II типа (I-клеточная болезнь) отличался более тяжелым течением. Клинический диагноз был подтвержден результатами лабораторных методов исследования: нормальными показателями почечной экскреции гликозаминогликанов (ГАГ), высокой (в 5-15 раз выше нормы) активностью лизосомных гидролаз в плазме крови и выявлением мутаций в гене GNPTAB. Полностью генотипированы 35 пробандов. У 8 больных выявлено только 8 мутантных аллелей; у 7-мутации не обнаружены. Найдено 6 новых мутаций в экзонах 1 (p.I31N; p.Q36P), 10 (p.L398P), 11 (p.W446X) и 13 (p.S738X; c.2250delT), в том числе частая для российских больных мутация p.S738X (21% аллелей). Наиболее частой (31,4% аллелей) в российской когорте пациентов оказалась известная мелкая делеция c. 3503_3504delTC, приводящая к сдвигу рамки считывания. Представлено клиническое наблюдение ребенка с муколипидозом II типа (I-клеточная болезнь) с типичной симптоматикой заболевания, обусловленной двумя нонсенс-мутациями гена GNPTAB: p.S738X/p.R375X. В заключение подчеркивается, что идентификация мутаций гена GNPTAB обеспечивает прогнозирование тяжести течения болезни, понимание механизмов ее развития, что будет способствовать разработке методов патогенетического лечения, улучшению качества жизни больных и эффективному медико-генетическому консультированию.
Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.
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