Responsible Genes for Neuronal Migration in the Chromosome 17p13.3: Beyond Pafah1b1(Lis1), Crk and Ywhae(14-3-3ε)

The 17p13.3 chromosome region is often deleted or duplicated in humans, resulting in severe neurodevelopmental disorders such as Miller–Dieker syndrome (MDS) and 17p13.3 duplication syndrome. Lissencephaly can also be caused by gene mutations or deletions of a small piece of the 17p13.3 region, including a single gene or a few genes. PAFAH1B1 gene, coding for LIS1 protein, is a responsible gene for lissencephaly and MDS and regulates neuronal migration by controlling microtubules (MTs) and cargo transport along MTs via dynein. CRK is a downstream regulator of the reelin signaling pathways and regulates neuronal migration. YWHAE, coding for 14-3-3ε, is also responsible for MDS and regulates neuronal migration by binding to LIS1-interacting protein, NDEL1. Although these three proteins are known to be responsible for neuronal migration defects in MDS, there are 23 other genes in the MDS critical region on chromosome 17p13.3, and little is known about their functions in neurodevelopment, especially in neuronal migration. This review will summarize the recent progress on the functions of LIS1, CRK, and 14-3-3ε and describe the recent findings of other molecules in the MDS critical regions in neuronal migration.

Characterizing the variation in chromosome structure ensembles in the context of the nuclear microenvironment

Inside the nucleus, chromosomes are subjected to direct physical interaction between different components, active forces, and thermal noise, leading to the formation of an ensemble of three-dimensional structures. However, it is still not well understood to what extent and how the structural ensemble varies from one chromosome region or cell-type to another. We designed a statistical analysis technique and applied it to single-cell chromosome imaging data to reveal the fluctuation of individual chromosome structures. By analyzing the resulting structural landscape, we find that the largest dynamic variation is the overall radius of gyration of the chromatin region, followed by domain reorganization within the region. By comparing different human cell-lines and experimental perturbations data using this statistical analysis technique and a network entropy approach, we identify both cell-type and condition-specific features of the structural landscapes. We identify a relationship between epigenetic state and the properties of chromosome structure fluctuation and validate this relationship through polymer simulations. Overall, our study suggests that the types of variation in a chromosome structure ensemble are cell-type as well as region-specific and can be attributed to constraints placed on the structure by factors such as variation in epigenetic state.

Alteration of serum leptin and LEP/LEPR promoter methylation in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder based on a loss of paternally expressed but maternally imprinted genes in chromosome region 15q11-13. During child development, PWS usually results in insatiable appetite with subsequent obesity representing the major mortality factor. The neurobiological basis of PWS-typical hyperphagia has remained poorly understood. Many PWS-typical abnormalities are based on hypothalamic dysregulation, the region in which hunger and satiety are hormonally regulated, with the hormone leptin being a main long-term regulator of satiety. Previous studies in PWS have inconsistently shown leptin alterations solely in early childhood, without investigating the leptin system on an epigenetic level. The present study investigates serum leptin levels (S-leptin) and methylation of the leptin (LEP) and leptin receptor gene (LEPR) promoter in 24 individuals with PWS compared to 13 healthy controls matched for sex, age, and body mass index (BMI) and relates the results to the extent of hyperphagia in PWS. S-Leptin levels were obtained by Enzyme-linked Immunosorbent Assay. LEP/LEPR-promoter methylation was assessed by DNA-bisulfite-sequencing, hyperphagia by Hyperphagia Questionnaire for Clinical Trials (HQ-CT). PWS and control groups differed significantly in S-leptin levels with higher S-leptin in PWS. Methylation analysis showed significant differences in mean promoter methylation rate both for LEP and LEPR with a lower methylation rate in PWS. LEPR, but not LEP methylation correlated with S-leptin levels. S-leptin and both LEP and LEPR methylation did not correlate with HQ-CT scores in PWS. The present study is the first to show significantly elevated S-leptin levels in an adult PWS cohort combined with an altered, downregulated LEP and LEPR promoter methylation status compared to BMI-matched controls. Analogous to previous studies, no link to the behavioral dimension could be drawn. Overall, the results suggest an increased leptin dysregulation in PWS, whereby the findings partly mirror leptin resistance seen in non-syndromic obesity.

PRADER-WILLI SYNDROME: A CLINICAL CASE

Синдром Прадера-Вилли - редкое наследственное заболевание, причиной которого является отсутствие отцовской копии участка хромосомы 15q11-13. Одним из проявлений данного генетического синдрома может быть соматотропная недостаточность. Именно низкорослость часто является поводом для обращения родителей пациента к врачу-эндокринологу. Для своевременной диагностики заболевания очень важен командный подход специалистов с участием генетика, эндокринолога, невропатолога с обязательным проведением генетического анализа. Обнаружение дефицита гормона роста и назначение соответствующей заместительной терапии повышает уровень медицинской и социальной адаптации ребенка. В данной статье описан случай синдрома Прадера-Вилли с соматотропной недостаточностью у 4-летней девочки, представлены преимущества и риски применения гормона роста. Prader-Willi syndrome is a rare hereditary disorder caused by the absence of a paternal copy of the 15q11-13 chromosome region. One of the manifestations of this genetic syndrome may be somatotropic insufficiency. It is the short stature that is often the reason for the patient's parents to contact an endocrinologist. For the timely diagnosis of the disease, a team approach of specialists with the participation of a geneticist, endocrinologist, neuropathologist with the obligatory genetic analysis is very important. Detection of growth hormone deficiency and the appointment of appropriate substitution therapy increases the level of medical and social adaptation of the child. This article describes a case of Prader-Willi syndrome with growth hormone deficiency in a 4-year-old girl, presents the benefits and risks of using growth hormone.

Case Report: Congenital Brain Dysplasia, Developmental Delay and Intellectual Disability in a Patient With a 7q35-7q36.3 Deletion

7q terminal deletion syndrome is a rare condition presenting with multiple congenital malformations, including abnormal brain and facial structures, developmental delay, intellectual disability, abnormal limbs, and sacral anomalies. At least 40 OMIM genes located in the 7q34-7q36.3 region act as candidate genes for these phenotypes, of which SHH, EN2, KCNH2, RHEB, HLXB9, EZH2, MNX1 and LIMR1 may be the most important. In this study, we discuss the case of a 2.5-year-old male patient with multiple malformations, congenital brain dysplasia, developmental delay, and intellectual disability. A high-resolution genome-wide single nucleotide polymorphism array and real-time polymerase chain reaction were performed to detect genetic lesions. A de novo 9.4 Mb deletion in chromosome region 7q35-7q36.3 (chr7:147,493,985–156,774,460) was found. This chromosome region contains 68 genes, some of which are candidate genes for each phenotype. To the best of our knowledge, this is a rare case report of 7q terminal deletion syndrome in a Chinese patient. Our study identifies a rare phenotype in terms of brain structure abnormalities and cerebellar sulcus widening in patients with deletion in 7q35-7q36.3.

Congenital amusia—pathology of musical disorder

Amusia also known as tone deafness affects roughly 1.5% population. Congenital amusia appears from birth and lasts over life span. Usually, it is not associated with other diseases. Its link to hearing impairment has been definitively excluded. Neurobiological studies point to asymmetrical processing of musical signals in auditory cortex of left and right brain hemispheres. The finding was supported by discovering microlesions in the right-side gray matter. Because of its connection with asymmetry, amusia has been classified to disconnection syndromes. Alternatively to the neurobiological explanation of amusia background, an attention was turned to the significance of genetic factors. The studies done on relatives and twins indicated familial aggregation of amusia. Molecular genetic investigations linked amusia with deletion of 22q11.2 chromosome region. Until now no specific genes responsible for development of amusia were found.

A Novel LC–MS/MS-Based Method for the Diagnosis of ADA2 Deficiency from Dried Plasma Spot

Adenosine Deaminase 2 Deficiency (DADA2) (OMIM: 607575) is a monogenic, autoinflammatory disease caused by the loss of functional homozygous or heterozygous mutations in the ADA 2 gene (previously CECR1, Cat Eye Syndrome Chromosome Region 1). A timely diagnosis is crucial to start Anti-TNF therapies that are efficacious in controlling the disease. The confirmation of DADA2 is based on DNA sequencing and enzymatic assay. It is, thus, very important to have robust and reliable assays that can be rapidly utilized in specialized laboratories that can centralize samples from other centers. In this paper, we show a novel enzymatic assay based on liquid chromatography-tandem mass spectrometry that allows the accurate determination of the ADA2 enzyme activity starting from very small amounts of plasma spotted on filter paper (dried plasma spot). The method allows significantly distinguishing healthy controls from affected patients and carriers and could be of help in implementing the diagnostic workflow of DADA2.

RanBP3 Regulates Proliferation, Apoptosis and Chemosensitivity of Chronic Myeloid Leukemia Cells via Mediating SMAD2/3 and ERK1/2 Nuclear Transport

Abnormal subcellular localization of proteins is an important cause of tumorigenesis and drug resistance. Chromosome region maintenance 1 (CRM1), the nuclear export regulator of most proteins, has been confirmed to be over-expressed in various malignancies and is regarded as an efficient target. But the potential role of the CRM1 cofactor RanBP3 (Ran Binding Protein 3) is left unrevealed in chronic myeloid leukemia (CML). Here, we first detected the level of RanBP3 in CML and found an elevated RanBP3 expression in CML compared with control. Then we used shRNA lentivirus to down-regulated RanBP3 in imatinib sensitive K562 cells and resistant K562/G01 cells and found RanBP3 silencing inhibited cell proliferation by up-regulating p21, induced caspase3-related cell apoptosis, and enhanced the drug sensitivity of IM in vitro. Notably, we observed that RanBP3 silencing restored imatinib sensitivity of K562 cells in NOD/SCID mice. Mechanistically, the nuclear aggregation of SMAD2/3 revealed that tumor suppressor axis (TGF-β)-SMAD2/3-p21 was the anti-proliferation program related to RanBP3 knockdown, and the decrease of cytoplasmic ERK1/2 caused by RanBP3 interference leaded to the down-regulation of anti-apoptosis protein p(Ser112)-BAD, which was the mechanism of increased cell apoptosis and enhanced chemosensitivity to imatinib in CML. In summary, this study revealed the expression and potential role of RanBP3 in CML, suggesting that targeting RanBP3 alone or combined with TKIs could improve the clinical response of CML.

Enlisting wild grass genes to combat nitrification in wheat farming: A nature-based solution

Active nitrifiers and rapid nitrification are major contributing factors to nitrogen losses in global wheat production. Suppressing nitrifier activity is an effective strategy to limit N losses from agriculture. Production and release of nitrification inhibitors from plant roots is termed “biological nitrification inhibition” (BNI). Here, we report the discovery of a chromosome region that controls BNI production in “wheat grass” Leymus racemosus (Lam.) Tzvelev, located on the short arm of the “Lr#3Nsb” (Lr#n), which can be transferred to wheat as T3BL.3NsbS (denoted Lr#n-SA), where 3BS arm of chromosome 3B of wheat was replaced by 3NsbS of L. racemosus. We successfully introduced T3BL.3NsbS into the wheat cultivar “Chinese Spring” (CS-Lr#n-SA, referred to as “BNI-CS”), which resulted in the doubling of its BNI capacity. T3BL.3NsbS from BNI-CS was then transferred to several elite high-yielding hexaploid wheat cultivars, leading to near doubling of BNI production in “BNI-MUNAL” and “BNI-ROELFS.” Laboratory incubation studies with root-zone soil from field-grown BNI-MUNAL confirmed BNI trait expression, evident from suppression of soil nitrifier activity, reduced nitrification potential, and N2O emissions. Changes in N metabolism included reductions in both leaf nitrate, nitrate reductase activity, and enhanced glutamine synthetase activity, indicating a shift toward ammonium nutrition. Nitrogen uptake from soil organic matter mineralization improved under low N conditions. Biomass production, grain yields, and N uptake were significantly higher in BNI-MUNAL across N treatments. Grain protein levels and breadmaking attributes were not negatively impacted. Wide use of BNI functions in wheat breeding may combat nitrification in high N input–intensive farming but also can improve adaptation to low N input marginal areas.