Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.

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Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS)

This book is one of our contemporary medical bibles. It needs no introduction; those who have frequent need of it know it very well, and those who use it less often seek it out on the library shelf when problems arise. The book is truly encyclopedic. Everything relevant discovered during the six-year intervals between publication finds its way into these pages. By today's standards, its 1,778 closely packed small-print pages are a bargain. The mutant gene is both hero and villain in this book. It is reponsible for the biochemical abnormality that results in disease, no matter how rare a given abnormality may be. By the same token, however, it is truly an experiment of nature, shedding light on fundamental metabolic sequences and biologic mechanisms. This volume, more than most, explains the contributions of the laboratory to clinical medicine. Each chapter seems to have been rewritten, so that the exciting

The Metabolic Basis Of Inherited Disease.

In this age of modern era, the use of internet must be maximized. Yeah, internet will help us very much not only for important thing but also for daily activities. Many people now, from any level can use internet. The sources of internet connection can also be enjoyed in many places. As one of the benefits is to get the on-line analysis of human genetic linkage book, as the world window, as many people suggest.

Analysis of human genetic linkage

Neurodevelopmental models of schizophrenia that identify longitudinal precursors of illness have been of great heuristic importance focusing most etiologic research over the past two decades. These models have varied considerably with respect to specificity and timing of hypothesized genetic and environmental 'hits', but have largely focused on insults to prenatal brain development. With heritability around 80%, nongenetic factors impairing development must also be part of the model, and any model must also account for the wide range of age of onset. In recent years, longitudinal brain imaging studies of both early and adult (to distinguish from late ie elderly) onset populations indicate that progressive brain changes are more dynamic than previously thought, with gray matter volume loss particularly striking in adolescence and appearing to be an exaggeration of the normal developmental pattern. This supports an extended time period of abnormal neurodevelopment in schizophrenia in addition to earlier 'lesions'. Many subtle cognitive, motor, and behavioral deviations are seen years before illness onset, and these are more prominent in early onset cases. Moreover, schizophrenia susceptibility genes and chromosomal abnormalities, particularly as examined for early onset populations (ie GAD1, 22q11DS), are associated with premorbid neurodevelopmental abnormalities. Several candidate genes for schizophrenia (eg dysbindin) are associated with lower cognitive abilities in both schizophrenic and other pediatric populations more generally. Postmortem human brain and developmental animal studies document multiple and diverse effects of developmental genes (including schizophrenia susceptibility genes), at sequential stages of brain development. These may underlie the broad array of premorbid cognitive and behavioral abnormalities seen in schizophrenia, and neurodevelopmental disorders more generally. Increased specificity for the most relevant environmental risk factors such as exposure to prenatal infection, and their interaction with susceptibility genes and/or action through phase-specific altered gene expression now both strengthen and modify the neurodevelopmental theory of schizophrenia.

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The neurodevelopmental model of schizophrenia: update 2005.

Bone morphogenetic proteins (BMPs) exhibit broad spectra of biological activities in various tissues, including bone, cartilage, blood vessels, heart, kidney, neurons, liver and lung. BMPs are members of the transforming growth factor-beta (TGF-beta) family that bind to type II and type I serine-threonine kinase receptors, and transduce signals through Smad and non-Smad signalling pathways. Recent findings have revealed that BMP signalling is finely tuned by various mechanisms in both positive and negative fashions. Perturbations of BMP signalling pathways are linked to a wide variety of clinical disorders, including vascular diseases, skeletal diseases and cancer. Administration of recombinant BMP ligands and increasing endogenous expression of BMPs provide therapeutic effects on some diseases. The recent development of BMP receptor inhibitors may also prove useful for some clinical diseases induced by hyperactivation of the BMP signalling pathways.

/pdf/bone-morphogenetic-protein-receptors-and-signal-transduction-b4r31kj7gs.pdf

Bone morphogenetic protein receptors and signal transduction

We present a patient with acromesomelic chondrodysplasia and genital anomalies caused by a novel homozygous mutation in BMPR1B, the gene coding for bone morphogenetic protein receptor 1B. The 16 year old girl, the offspring of a multiconsanguinous family, showed a severe form of limb malformation consisting of aplasia of the fibula, severe brachydactyly, ulnar deviation of the hands, and fusion of carpal/tarsal bones. In addition, she presented with hypoplasia of the uterus and ovarian dysfunction resulting in hypergonadotrophic hypogonadism. Mutation analysis of BMPR1B revealed a homozygous 8 bp deletion (del359-366). This mutation is expected to result in a loss of function and is thus different from the heterozygous missense mutations in BMPR1B recently shown to cause brachydactyly type A2 through a dominant negative effect. The patient's skeletal phenotype shows an overlap with the clinical spectrum of the acromesomelic chondrodysplasias of the Grebe, Hunter-Thompson, and DuPan types caused by homozygous mutations in the gene coding for growth differentiation factor 5 (GDF5) which is a high-affinity ligand to BMPR1B. However, the phenotype described here differs from GDF5 associated chondrodysplasias because of the additional presence of genital anomalies and the distinct limb phenotype.

https://jmg.bmj.com/content/jmedgenet/42/4/314.full.pdf

A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies

The objective of this study was to evaluate the relationship between humoral and cell-mediated immune response parameters and impairment of immune functions in children with Down syndrome (DS). The patient group was consisted of cytogenetically documented 32 children with DS. Lymphocyte subsets and natural killer cells were counted by flow-cytometry system. Levels of interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10 and tumour necrosis factor-alpha (TNF-alpha) were detected by enzyme-linked immunosorbent assay method. Serum IgG, IgM, IgA levels were measured by turbidimetric methods. The percentage of CD8+ lymphocytes and CD56+ cells of patients with DS were significantly higher, whereas CD20+ lymphocytes were lower than that of controls (P 0.05). Levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-alpha levels were decreased in children with DS (P 0.05, for all). Serum IgG, IgM and IgA levels were found to be similar between the groups (P > 0.05). It has been known that IL-4 and IL-10 are anti-inflammatory molecules which inhibit the synthesis of proinflammatory cytokines such as IL-6 and TNF-alpha. In this study, levels of IL-4 and IL-10 were significantly increased, but IL-6 and TNF-alpha levels were decreased in children with DS. These results may suggest that continuing anti-inflammatory state in DS and this process may explain the cause of recurrent infection of the disease. On the other hand, in contrast to the low percentage of CD20+ cells, high percentage of CD8+ and CD56+ cells were found. Our findings may demonstrate that the cell-mediated and humoral immune system parameters in children with DS were altered according to healthy children.

Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome

The cerebellum is the primary motor coordination centre of the central nervous system. Lesions or congenital defects of the cerebellum cause incoordination of the muscles resulting in irregular gait and falling. Recently, we reported a large family with cerebellum hypoplasia and quadrupedal locomotion as a recessive trait, which we mapped to chromosome 17p13. We identified one additional family with the same condition and mapped the underlying gene to a 14-cM interval on chromosome 9ptel using a genome-wide linkage approach. Sequencing of candidate genes identified a homozygous frameshift mutation in the very low-density lipoprotein receptor (VLDLR) gene in all affected individuals. The association of cerebellar hypoplasia with mutations in VLDLR has been reported previously in the Hutterite population and in a family from Iran. However, quadrupedal locomotion was never observed indicating that environmental factors play a major role in the pathogenesis of this form of locomotion.

/pdf/cerebellar-hypoplasia-with-quadrupedal-locomotion-caused-by-12reudc315.pdf

Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.

Chromosome aberrations in a schizophrenia population.

Recently the gene responsible for Pendred syndrome (PDS) was isolated and several mutations in the PDS gene have been identified in Pendred patients. Here we report the occurrence of two different PDS mutations in an extended inbred Turkish family. The majority of patients in this family are homozygous for a splice site mutation (1143-2A-->G) affecting the 3' splice site consensus sequence of intron 7. However, two affected sibs with non-consanguineous parents are compound heterozygotes for the splice site mutation and a missense mutation (1558T-->G), substituting an evolutionarily conserved amino acid. The latter mutation has been found previously in two Pendred families originating from The Netherlands, indicating that the 1558T-->G mutation may be a common mutation.

https://jmg.bmj.com/content/jmedgenet/36/6/475.full.pdf

Osman Demirhan

Papers

A homozygous BMPR1B mutation causes a new subtype of acromesomelic chondrodysplasia with genital anomalies

Analysis of peripheral blood T-cell subsets, natural killer cells and serum levels of cytokines in children with Down syndrome

Cerebellar hypoplasia, with quadrupedal locomotion, caused by mutations in the very low-density lipoprotein receptor gene.

Chromosome aberrations in a schizophrenia population.

Identification of two different mutations in the PDS gene in an inbred family with Pendred syndrome