Chromosomal defects are one of the most common causes of genetic disorders and are responsible for a large proportion of miscarriages. As a result, more and more parents are becoming interested in genetic counseling in order to learn about the risks of reproductive failure, or to understand why they had a child with a particular defect, whether it will happen again, and what might be done to prevent it. This book addresses these and other questions concerning chromosome abnormalities. Although the book is written primarily for genetic counselors and laboratory workers in cytogenetics, it will be of interest to all physicians concerned with genetic counseling. Each chapter discusses a different type of defect, such as translocations, duplications, insertions, deletions, and non-disjunction. The basic biological theory underlying the problem is discussed and in-depth information is provided on the reproductive risks of chromosomally abnormal individuals and of normal parents who have a child with a chromosome abnormality. The book will help concerned parents determine an appropriate course of action, including prenatal diagnosis, and help counselors to communicate the information necessary for responsible decision-making.
We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1Δ18/Δ18), encoding inositol 1,4,5-triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in-frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 5′ part of the ITPR1 gene, encompassing exons 1–10, 1–40, and 1–44 in three studied families, underlies SCA15 in humans.
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