Клинико-генетические характеристики синдрома контрактур конечностей и лица, гипотонии и задержки психомоторного развития (OMIM:616 266), обусловленного мутациями в гене NALCN

A description of the clinical and genetic characteristics of the syndrome of congenital contractures of the limbs and face in combination with muscular hypotonia and psychomotor retardation of 2 patients from Russia is presented. As a result of full-exome DNA sequencing, 2 heterozygous missense mutations c 4355T C and c.3541C G were found in the NALCN gene, leading to amino acid substitutions at the functionally important center of the protein molecule. The effect of identified mutations in the NALCN gene on the function of its protein and approaches to the differential diagnosis of congenital contracture syndrome of the extremities and face in combination with muscular hypotonia and psychomotor retardation with monogenic variants of distal arthrogryposis with autosomal dominant type of inheritance are discussed.Представлено описание клинико-генетических характеристик синдрома врожденных контрактур конечностей и лица в сочетании с мышечной гипотонией и задержкой психомоторного развития 2 пациентов из России. В результате полноэкзомного секвенирования ДНК у пациентов обнаружены 2 гетерозиготные миссенс-мутации c.4355T>C и c.3541C>G в гене NALCN, приводящие к аминокислотным заменам в функционально значимом центре белковой молекулы. Обсуждается влияние выявленных мутаций в гене NALCN на функцию его белка и подходы к дифференциальной диагностике синдрома врожденных контрактур конечностей и лица в сочетании с мышечной гипотонией и задержкой психомоторного развития с моногенными вариантами дистальных артрогрипозов с аутосомно-доминантным типом наследования

Клинико-генетические характеристики ранней эпилептической энцефалопатии 66‑го типа (обзор литературы и собственное наблюдение)

Early epileptic encephalopathy-66 was first diagnosed in a male patient from Russia using whole-exome sequencing. Early epileptic encephalopathy- 66 is a unique disorder in the group of early epileptic encephalopathies. The same recurrent heterozygous variant of the nucleotide sequence was found in all known patients, but the severity of seizures and dysmorphic signs significantly vary between patients. The current study of a recurrent pathogenic variant in PACS2 gene expands the phenotype spectrum of early epileptic encephalopathy-66 and will improve the management of patients with that disorder in Russia in the future.Представлено первое описание клинико-генетических характеристик российского больного с ранней эпилептической энцефалопатией 66‑го типа. С помощью полноэкзомного секвенирования обнаружена ранее описанная гетерозиготная мутация NM_001100913.2: c.625G>A (p.Glu209Lys) в гене PACS2. Данное моногенное заболевание является уникальным в группе ранних эпилептических энцефалопатий – у всех пациентов обнаруживается одинаковый патогенный вариант нуклеотидной последовательности, но клинические проявления отличаются по степени тяжести и выраженности дизморфических признаков, что пред- положительно обусловлено разным генетическим фоном. Клиническое изучение серий случаев рекуррентных патогенных вариантов позволяет оптимизировать тактику ведения новых пациентов при обнаружении уже известного генетического варианта

Clinical and genetic characteristics of the syndrome of contractures of the limbs and face, hypothony and psychomotor retardation (OMIM: 616 266), caused by mutations in the NALCN gene

A description of the clinical and genetic characteristics of the syndrome of congenital contractures of the limbs and face in combination with muscular hypotonia and psychomotor retardation of 2 patients from Russia is presented. As a result of full-exome DNA sequencing, 2 heterozygous missense mutations c 4355T C and c.3541C G were found in the NALCN gene, leading to amino acid substitutions at the functionally important center of the protein molecule. The effect of identified mutations in the NALCN gene on the function of its protein and approaches to the differential diagnosis of congenital contracture syndrome of the extremities and face in combination with muscular hypotonia and psychomotor retardation with monogenic variants of distal arthrogryposis with autosomal dominant type of inheritance are discussed

Cluster organization of ion channels formed by the antibiotic syringomycin E in bilayer lipid membranes.

The cyclic lipodepsipeptide, syringomycin E, when incorporated into planar lipid bilayer membranes, forms two types of channels (small and large) that are different in conductance by a factor of sixfold. To discriminate between a cluster organization-type channel structure and other possible different structures for the two channel types, their ionic selectivity and pore size were determined. Pore size was assessed using water-soluble polymers. Ion selectivity was found to be essentially the same for both the small and large channels. Their reversal (zero current) potentials with the sign corresponding to anionic selectivity did not differ by more than 3 mV at a twofold electrolyte gradient across the bilayer. Reduction in the single-channel conductance induced by poly(ethylene glycol)s of different molecular weights demonstrated that the aqueous pore sizes of the small and large channels did not differ by more than 2% and were close to 1 nm. Based on their virtually identical selectivity and size, we conclude that large syringomycin E channels are clusters of small ones exhibiting synchronous opening and closing

Clinical and genetic characteristics of the early 66th type epileptic encephalopathy (literature review and own observation)

Early epileptic encephalopathy-66 was first diagnosed in a male patient from Russia using whole-exome sequencing. Early epileptic encephalopathy- 66 is a unique disorder in the group of early epileptic encephalopathies. The same recurrent heterozygous variant of the nucleotide sequence was found in all known patients, but the severity of seizures and dysmorphic signs significantly vary between patients. The current study of a recurrent pathogenic variant in PACS2 gene expands the phenotype spectrum of early epileptic encephalopathy-66 and will improve the management of patients with that disorder in Russia in the future

Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy.

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuromuscular disease and is characterized by considerable clinical and genetic heterogeneity. We previously reported a Russian family with autosomal dominant axonal CMT and assigned the locus underlying the disease (CMT2F; OMIM 606595) to chromosome 7q11-q21 (ref. 2). Here we report a missense mutation in the gene encoding 27-kDa small heat-shock protein B1 (HSPB1, also called HSP27) that segregates in the family with CMT2F. Screening for mutations in HSPB1 in 301 individuals with CMT and 115 individuals with distal hereditary motor neuropathies (distal HMNs) confirmed the previously observed mutation and identified four additional missense mutations. We observed the additional HSPB1 mutations in four families with distal HMN and in one individual with CMT neuropathy. Four mutations are located in the Hsp20-alpha-crystallin domain, and one mutation is in the C-terminal part of the HSP27 protein. Neuronal cells transfected with mutated HSPB1 were less viable than cells expressing the wild-type protein. Cotransfection of neurofilament light chain (NEFL) and mutant HSPB1 resulted in altered neurofilament assembly in cells devoid of cytoplasmic intermediate filaments