Genetics of the nephrotic syndrome

There are a large number of glomerular diseases that may be responsible for a nephrotic syndrome, the most frequent in childhood being minimal change disease. In the past few years, the molecular genetic basis of several conditions that may cause a nephrotic syndrome have been identified. Denys-Drash syndrome and Frasier syndrome are related diseases caused by mutations in the WT1 gene. Familial forms of idiopathic nephrotic syndrome with focal and segmental glomerular sclerosis/hyalinosis have been identified with an autosomal dominant or recessive mode of inheritance and linkage analysis have allowed to localize several genes on chromosomes 1, 11 and 17. The gene responsible for the Finnish type congenital nephrotic syndrome has been identified. This gene, named NPHS1, codes for nephrin, which is located at the slit diaphragm of the glomerular podocytes and is thought to play an essential role in the normal glomerular filtration barrier.     

MOLECULAR GENETICS OF PEROXISOMAL DISORDERS

Twenty five human peroxisomal disorders have been defined at this time. They are subdivided into two major categories: 1) the disorders of peroxisome biogenesis, in which the organelle fails to form normally, and there are defects that involve multiple peroxisomal functions; and 2) disorders that affect single peroxisomal enzymes. During the last five years the molecular defects have been identified in nearly all. These recent advances have several important implications. They have facilitated diagnosis of affected patients. The improved capacity to provide prenatal diagnosis and heterozygote identification has been of great value for genetic counseling and disease prevention. Study of genotype-phenotype correlations has led to a new and more rational classification system. The identification of the molecular defects and the development of animal models have increased understanding of pathogenetic mechanisms, and have led to novel therapeutic approaches.     

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction.     

Glut1 deficiency: When to suspect and how to diagnose?

Impaired glucose transport across the blood-brain barrier results in GLUT1 deficiency syndrome (GLUT1-DS), characterized by infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and hypoglycorrhachia. A part from this classic phenotype, clinical conditions associated with a deficiency of GLUT1 are highly variable and several atypical variants have been described; in particular, patients with movement disorders, but without seizures, with paroxysmal exertion-induced dyskinesia, have been reported.Most patients carry heterozygous de novo mutations in the GLUT1-gene but autosomal dominant and recessive transmission has been identified.Diagnosis is based on low cerebrospinal fluid glucose, in the absence of hypoglycemia, and it is confirmed by molecular analysis of the GLUT1-gene and by glucose uptake studies and immunoreactivity in human erythrocytes. Treatment with a ketogenic diet results in marked improvement of seizures and movement disorders.This review summarizes recent advances in understanding of GLUT1-DS and highlights the diagnostic and therapeutic approach to GLUT1-DS.     

遗传性肾病综合征的基因诊断

近年来,遗传性肾病综合征相关基因的陆续发现或为肾脏病学领域的一个突破性进展,目前约有18个与遗传性肾病综合征有关的基因已经被克隆、定位,相信将会有更多的基因陆续被发现,这些基因是大多数遗传性肾病综合征的病因。遗传性肾病综合征的分子生物学进展有助于该病诊断和治疗。遗传性肾病综合征的治疗方案复杂,常规治疗方案无效(包括激素和免疫抑制剂),因此很有必要理解并明确该类疾病的定义、分子遗传学分类、临床特征以及肾脏病理等相关进展。该文综述了遗传性肾病综合征的常见分子生物学、临床及病理特征,以期建立遗传性肾病综合征的基因诊断思路。     

脑性瘫痪的遗传学研究进展

脑性瘫痪(简称脑瘫)是由发育中的胎儿或婴幼儿脑部非进行性损伤所致一组症候群,是导致儿童时期残疾的主要疾病,脑瘫病因学研究一直是临床科学家关注的焦点。越来越多的证据表明,遗传因素与脑瘫的发病密切相关。近年来,随着染色体微阵列分析、全基因组扫描和全外显子测序等分子生物技术的发展和应用,脑瘫的遗传学研究取得了许多新进展,发现了大量与脑瘫发病相关的染色体异常、基因组拷贝数变异、易感基因及单基因突变等,为脑瘫发病机制的研究提供了新的机遇。现就近年来脑瘫的遗传学病因研究进展作一综述。     

Human disorders of ubiquitination and proteasomal degradation

PURPOSE OF REVIEW: The goal of this review is to provide an overview of rapidly evolving information on a new group of genetic inborn errors affecting ubiquitination and proteasomal degradation of proteins and to suggest a classification scheme for these disorders. The relevant genes encode ubiquitin, ubiquitin enzymes (E1 and many E2s and E3s), deubiquitinating enzymes, proteasomal subunits, and substrates undergoing ubiquitination. RECENT FINDINGS: Since the initial recognition that Angelman syndrome is caused by maternal deficiency of the E6-AP ubiquitin E3 ligase (gene symbol UBE3A), several. other disorders of E3 ligases have been identified, including autosomal recessive juvenile Parkinson disease, the APECED form of autoimmune polyendocrinopathy syndrome, von Hippel-Lindau syndrome, and congenital polycythemia. Disorders that disturb ubiquitin regulatory signaling include at least two subtypes of Fanconi anemia, the BRCA1 and BRCA2 forms of breast and ovarian cancer susceptibility, incontinentia pigmenti, and cylindromatosis. Many disorders affect ubiquitin pathways secondarily. SUMMARY: The authors propose both a genetic and a functional classification for disorders of ubiquitination and proteasomal degradation, as follows. Genetic classes include mutations in (1) the UBB ubiquitin gene; (2) enzymes of ubiquitination including E1, E2, E3, and related proteins; (3) deubiquitinases; (4) proteasomal subunits; and (5) substrates of ubiquitination. Functional classes include defects in (1) proteolytic degradation, (2) ubiquitin signaling, and (3) subcellular localization of substrates. Additional functional classes are likely to be defined, and individual disorders may involve multiple functional defects.     

Achondroplasia: Recent advances in diagnosis and treatment

Achondroplasia (ACH) is the most common form of chondrodysplasia in humans. This disorder is inherited as an autosomal dominant trait, though most cases are sporadic. Recent advances in molecular biology have revealed its genetic defect in fibroblast growth factor-3 gene. This may introduce a new diagnostic tool and the classification of ACH and related disorders. Recent molecular engineering techniques have made it possible to provide large amounts of the various kinds of biofactors, such as erythropoietin, granulocyte colony stimulating factor and human growth hormone (GH), for clinical use. In fact, GH has been widely used to treat non-GH-deficient forms of short stature, such as Turner's syndrome, skeletal dysplasia, intrauterine growth retardation, chronic illness and idiopathic short stature, with beneficial effects. This may also be introduced into the medical management of ACH.     

Prenatal diagnosis and carrier detection of inherited immunodeficiency disorders

Clinical immunodeficiency states may arise as a consequence of genetic defects in the immune system. An increasing number of such diseases are now being identified and in some cases the underlying defects are well understood. In some disorders the outlook has been improved by advances in available treatment, but in most the prognosis is still very poor with death in early infancy in many cases. Recently, there have been significant advances in techniques for prenatal diagnosis and carrier detection for some of these disorders. These include the use of gene tracking by restriction fragment length polymorphism (RFLP) and deletion analysis, detection of defective gene products, assessment of cellular dysfunction, cell series analysis, and X-chromosome inactivation studies for carrier detection.     

Molecular genetics in childhood hypertension

Significant progress has been made in recent years in the elucidation of the molecular genetic basis for several rare forms of hypertension that are often first diagnosed in childhood. This review summarizes these findings. Glucocorticoid remediable aldosteronism has been shown to be caused by unequal crossing over between the genes for 11β-hydroxylase and aldosterone synthase so that corticotropin (ACTH) becomes the major controller of the latter enzyme activity, meaning greatly elevated aldosterone synthesis and thus sodium retention, volume expansion and high blood pressure. Mutations in the 11β-hydroxylase gene are the cause of 11β-hydroxylase deficiency, another form of childhood hypertension. Apparent mineralocorticoid excess has been found to involve mutation of the gene encoding 11β-hydroxysteroid dehydrogenase type 2, which means instead of being destroyed in aldosterone target cells in the kidney, cortisol is able to bind to the mineralocorticoid receptor, leading to greatly enhanced sodium reabsorption by the kidney. Liddle's syndrome is another condition seen early in life and can involve mutations in the carboxyl terminal region of the β- or γ-subunits of the amiloride-sensitive epithelial sodium channel gene. This prevents binding of a protein that tags the channel for endocytosis and degradation so that channel activity is increased. Other forms of hypertension of early onset such as Gordon's syndrome, pheochromocytoma and brachydactyly are also discussed. The review thus highlights the major advances that have occurred in understanding the molecular basis for various forms of hypertension seen in children.     

Advances in understanding the genetic basis for bone-marrow failure

PURPOSE OF REVIEW: Inherited marrow failure syndromes (IMFSs) are rare genetic diseases with varying degrees of cytopenia. Many of the syndromes are also characterized by nonhematological manifestations and a high risk of cancer. This review summarizes recent advances in understanding the genetic background of the common IMFSs. RECENT FINDINGS: Over recent years, numerous known and novel genes have been found to be associated with IMFSs. Although the functions of the proteins are largely unknown, they are postulated to play critical roles in fundamental cellular processes such as DNA repair, telomere maintenance, RNA metabolism, ribosomal biogenesis, growth-factor-signaling pathways and cell survival. For example, the telomere-related genes, DKC1 and TERC, have been identified as causes of dyskeratosis congenita. Also, homozygosity for the common cancer-associated gene, BRCA2, has been found to cause a rare subtype of Fanconi anemia. SUMMARY: The knowledge of the genetics of IMFSs has started to be translated into clinical practice. The identification of IMFS-related genes provided new diagnostic tools and better classification of the various disorders. Also, these advances enabled the design of clinical trials using gene therapy and preimplantation genetic diagnosis followed by in-vitro fertilization for selection of suitable embryos for hematopoietic stem-cell transplantation.     

Differential diagnosis of type 1 diabetes: which genetic syndromes need to be considered?

Abstract:  Recently it has become apparent that not all diabetes presenting in childhood is type 1. Increasingly type 2 diabetes, secondary diabetes, maturity onset diabetes of the young, and rare syndromic forms of diabetes such as Wolfram syndrome and Alstrom syndrome have been identified in children. Although individually rare, collectively they make up about 5% of children seen in diabetes clinics. The importance of these syndromes for children lies in the recognition of treatable complications, and for their parents, the possibility of genetic counselling. The scientific importance is enormous as they are experiments of nature that reveal basic mechanisms of insulin and glucose metabolism. We are now able to offer mutation analysis to correlate the clinical pattern to the genotype, and seek novel therapeutic approaches based on the developing knowledge of gene and protein functions. This review focuses on monogenic syndromes of diabetes, particularly where significant advances have been made in our understanding recently. Neonatal diabetes is a specialist field in its own right and is not included, except to discuss Kir6.2 diabetes which may develop in infancy. This review is written for the paediatric diabetes specialist and aims to provide information on the clinical features, natural history, genetics and management of children with diabetes as part of a syndrome. Finally there is information on useful investigations to aid diagnosis.     

Leukodystrophies: Indian scenario

The leukodystrophies are familial disorders with onset usually in infancy or childhood. The clinical features consist of motor dysfunction with varying degree of cognitive decline. Magnetic Resonance Imaging (MRI) has helped to identify and characterize these disorders. In some leukodystrophies, biochemical enzymatic and genetic defects have been identified. The commonest leukodystrophy seen in India is Megalencephalic Leukodystrophy with subcortical cysts. The essential features consist of large head, mild pyramidal and cerebellar dysfunction, and occasional seizures. MRI studies show extensive white matter changes with temporal cysts. It is common in the Agarwal community in India. An identical mutation in exon 2 of the MLC 1 gene has been identified in this community suggesting a founder effect     

Recent advances in understanding the genetic etiology of congenital heart disease.

The genetic etiologies of multiple cardiovascular disorders have been identified recently. For the most part, familial cardiomyopathic, vascular, or arrhythmogenic disorders have been studied given the opportunity to identify the disease gene by linkage analyses, positional cloning, and analysis of candidate genes. Given that structural congenital heart disease rarely occurs in the context of large families, alternative approaches to understand the possible genetic etiologies have been taken. In particular, molecular evaluations of genetic syndromes in which cardiac defects are a cardinal feature are providing new insights into disease-related genes and developmental pathways. The identification of rare families with multiple affected members also has provided some insight into the genetic contribution to structural congenital heart defects. This review highlights the newest findings on the genetic etiology or implications in each of the subcategories of congenital cardiovascular disorders, and will provide the reader with both a brief overview and update. Particular note will be made of the genotype/phenotype analyses of hypertrophic cardiomyopathy and the long QT syndromes, as well as the identification of new disease-related genes for dilated cardiomyopathy, idiopathic ventricular fibrillation, and structural heart disease.     

Rett syndrome: clinical and molecular update

PURPOSE OF REVIEW: New information on the clinical and molecular aspects of Rett syndrome has emerged at an accelerated pace since the identification of mutations in methyl-CpG-binding protein 2 gene (MECP2) was first reported in 1999. Recent reports not only present new insights into the clinical and molecular understanding of this unique disorder but also have important implications for the neurobiology beyond Rett syndrome. RECENT FINDINGS: This review covers recent advances in Rett syndrome from clinical management issues to laboratory-based genetic discoveries. SUMMARY: Clinical management issues include electrocardiographic findings, scoliosis, osteopenia, and motor control. Interesting phenotype-genotype correlations have resulted from the recognition of large-scale deletions in MECP2 as a cause of Rett syndrome, and the more recent identification of an alternate splicing isoform of the gene product. These are beginning to provide a more coherent picture of the spectrum of disease caused by mutations in MECP2. The neurobiologic role of the MECP2 gene in Rett syndrome and normal development has been greatly elucidated with the development of animal models of Rett syndrome and the study of MECP2 in humans and rodents.     

Genetics of pediatric neuromuscular disease

Our understanding of the neuromuscular disorders of childhood has been rapidly expanding. This is mostly because of the discovery of the underlying genetic loci for the vast majority of these diseases and the abnormal proteins produced caused by these mutations. Spinal muscular atrophy is the second most frequent autosomal recessive disease of childhood and the most fatal. It has been mapped to chromosome 5q11.2-13.3, an area with three distinct genes associated with spinal muscular atrophy. Charcot-Marie-Tooth is the most common inherited peripheral neuropathy. Three genes encoding for myelin proteins and one for a nuclear protein have been associated with this group of disorders. Finally, since dystrophin was cloned in 1986, many proteins assisting dystrophin in anchoring the muscle cytoskeleton to the extracellular matrix have been discovered. Mutations in these genes lead to various forms of muscular dystrophy.     

Genetic predisposition to necrotizing enterocolitis in premature infants: Current knowledge,challenges, and future directions

The role of genetics in the pathogenesis of necrotizing enterocolitis (NEC) was initially informed by epidemiological data indicating differences in prevalence among different ethnic groups as well as concordance in twins. These early observations, together with major advances in genomic research, paved the way for studies that begin to reveal the contribution of genetics to NEC. Using the candidate gene or pathway approach, several potential pathogenic variants for NEC in premature infants have already been identified. More recently, genome-wide association studies and exome-sequencing based studies for NEC have been reported. These advances, however, are tempered by the lack of adequately powered replication cohorts to validate the accuracy of these discoveries. Despite many challenges, genetic research in NEC is expected to increase, providing new insights into its pathogenesis and bringing the promise of personalized care closer to reality. In this review we provide a summary of genetic studies in NEC along with defining the challenges and possible future approaches.     

Molecular advances in genetic skin diseases

The genes for several genetic skin diseases have been identified in recent years. This development improves diagnostic capabilities and genetic counseling, and investigators can now turn to the molecular mechanisms involved in the pathogenesis of these diseases. The identification of the causative genes has led to the generation of mouse models for some genetic skin diseases. A study of the keratin 10 deficient mouse, a model for epidermolytic hyperkeratosis, and a mouse model for Bloom syndrome are reviewed in this article. Several studies also evaluate the relation between genotype and phenotype. In this article, the clinical findings and molecular advances in tuberous sclerosis complex, neurofibromatosis type 1, Bloom syndrome, epidermolytic hyperkeratosis, X-linked ichthyosis, Netherton syndrome, and Hermansky-Pudlak syndrome are reviewed.