The inheritance pattern of diseases due to unstable repeat expansions was presented in Chapter 7, with emphasis on the unusual genetics of this unique group of almost 60 disorders. These features include the unstable and dynamic nature of the variants, which arise from expansion of repeated sequences within the transcribed region of the affected gene. Examples include the codon for glutamine (CAG) in Huntington disease and in most of a group of neurodegenerative disorders called the spinocerebellar ataxias, or the codon for alanine (GCG) in diseases such as oculopharyngeal muscular dystrophy. The expansion can also be of trinucleotides in noncoding regions of RNAs, including CGG in fragile X syndrome, GAA in Friedreich ataxia, CUG in myotonic dystrophy 1 (Fig. 1), or GCA in glutaminase deficiency.

Fig1. The locations of the nucleotide repeat expansions and the sequence of each nucleotide in five representative nucleotide repeat diseases, shown on a schematic of a generic pre–messenger RNA (mRNA). The minimal number of repeats in the DNA sequence of the affected gene associated with the disease is also indicated. The effect of the expansion on the mutant RNA or protein is also indicated. (Based partly on an unpublished figure courtesy John A. Phillips III, Vanderbilt University Nashville.)

Although the nucleotide repeat diseases initially described are all due to the expansion of trinucleotide repeats, with the help of advanced genomic technologies, other disorders have been found to result from the expansion of longer repeats; these include a tetranucleotide (CCTG) in myotonic dystrophy 2 (a close genocopy of myotonic dystrophy 1), a pentanucleotide (ATTCT) in spinocerebellar atrophy 10, an inserted pentanucleotide (TTTCA) in a group of familial adult myoclonic epilepsies, and a hexanucleotide (GGGGCC) in amyotrophic lateral sclerosis. Because the affected gene is passed from generation to generation, the number of repeats may expand to a degree that is pathogenic, ultimately interfering with normal gene expression and function. The intergenerational expansion of the repeats accounts for the phenomenon of anticipation: the appearance of the disease at an earlier age or with more severe form as it is transmitted through a family. The biochemical mechanism most proposed to underlie the expansion of unstable repeat sequences is slipped mispairing (Fig. 2). Remarkably, the repeat expansions appear to occur both in proliferating cells, such as spermatogonia (during meiosis), and in nonproliferating somatic cells, such as neurons. Consequently, expan sion can occur – depending on the disease – during both DNA replication (as shown in Fig. 2) and genome maintenance (i.e., DNA repair).

Fig2. The slipped mispairing mechanism thought to underlie the expansion of unstable repeats, such as the (CAG)n repeat found in Huntington disease and the spinocerebellar ataxias. An insertion occurs when the newly synthesized strand aberrantly dissociates from the template strand during replication synthesis. When the new strand reassociates with the template strand, the new strand may slip back to align out of register with an incorrect repeat copy. Once DNA synthesis is resumed, the misaligned molecule will contain one or more extra copies of the repeat (depending on the number of repeat copies that slipped out in the misalignment event).

The clinical phenotypes of Huntington disease and fragile X syndrome are presented in Chapter 7 and in Cases 24 and 17, respectively. It has become apparent, particularly with fragile X syndrome, that diseases due to the expansion of unstable repeats are primarily neuro logic; the clinical presentations include ataxia, cognitive defects, dementia, nystagmus, parkinsonism, and spasticity. Nevertheless, other systems are sometimes involved, as illustrated by some of the diseases discussed here.

The Pathogenesis of Diseases Due to Unstable Repeat Expansions

Diseases of unstable repeat expansion are diverse in their pathogenic mechanisms. They can be divided into three main classes, considered in turn in the sections to follow.

• Class 1: diseases due to the expansion of noncoding repeats that cause a loss of protein expression

• Class 2: disorders resulting from expansions of noncoding repeats that confer novel properties on the RNA

• Class 3: diseases due to repeat expansion of a codon such as CAG (for glutamine) that confers novel properties on the affected protein

Class 1: Diseases Due to the Expansion of Noncoding Repeats That Cause a Loss of Protein Expression

 Fragile X Syndrome. In the X-linked fragile X syn drome, expansion of the CGG repeat in the 5′ untranslated region (UTR) of the FMR1 gene to more than 200 copies leads to excessive methylation of cytosines in the promoter; this epigenetic modification of the DNA silences transcription of the gene. Remarkably, the epigenetic silencing appears to be mediated by the variant FMR1 mRNA itself. The initial step in the silencing of FMR1 results from the FMR1 mRNA (containing the transcribed CGG repeat) hybridizing with the complementary CGG-repeat sequence of the FMR1 gene, to form an RNA:DNA duplex. The mechanisms that subsequently maintain the silencing of the FMR1 gene are unknown. The loss of the related protein (FMRP) is the cause of the intellectual disability, learning deficits, and nonneurologic features of the clini cal phenotype, including postpubertal macroorchidism and connective tissue dysplasia. FMRP is an RNA-binding protein that associates with polyribosomes to suppress the translation of proteins from its RNA tar gets. These targets appear to be involved in cytoskeletal structure, synaptic transmission, and neuronal maturation; disruption of these processes is likely to underlie the intellectual disability and learning abnormalities seen in individuals with fragile X. For example, FMRP appears to regulate the translation of proteins required for the formation of synapses because the brains of individuals with the fragile X syndrome have increased density of abnormally long, immature dendritic spines. Moreover, FMRP localizes to dendritic spines, where at least one of its roles is to regulate synaptic plasticity – the capacity to alter the strength of a synaptic connection – a process critical to learning and memory.

Fragile X Tremor/Ataxia Syndrome. Remarkably, in individuals with less pronounced CGG repeat expansion (60–200 repeats) in the FMR1 gene, causing the clinically distinct fragile X tremor/ataxia syndrome (FXTAS), the pathogenesis is entirely different from that of the fragile X syndrome itself. Although decreased translational efficiency impairs the expression of FMRP in FXTAS, this reduction cannot be responsible for the disease because males with full expansions and virtu ally complete loss of function of the FMR1 gene never develop FXTAS. Rather, FXTAS seems to result from the two- to fivefold increase of FMR1 mRNA in these patients, representing a gain-of-function variant. This pathogenic RNA leads to the formation of intranuclear neuronal inclusions, the cellular signature of the disease.

Class 2: Disorders Resulting From Expansions of Noncoding Repeats That Confer Novel Properties on the RNA

 Myotonic Dystrophy. Myotonic dystrophy 1 (DM1) is an autosomal dominant condition with the most pleiotropic phenotype of all the unstable repeat expansion disorders. In addition to myotonia, it is characterized by muscle weakness and wasting, cardiac conduction defects, testicular atrophy, insulin resistance, and cataracts; there is also a congenital form with intellectual disability. The disease results from a CTG expansion in the 3′ UTR of the DMPK gene, which encodes a protein kinase (see Fig. 1). Myotonic dystrophy 2 (DM2) is also an autosomal dominant trait and shares most of the clinical features of DM1, except that there is no associated congenital presentation. DM2 is due to the expansion of a CCTG tetranucleotide in the first intron of the gene encoding zinc finger protein 9 (see Fig. 1). The strikingly similar phenotypes of DM1 and DM2 suggest that they have a common pathogenesis. Because the unstable expansions occur within the noncoding regions of two different genes that encode unrelated proteins, the CTG trinucleotide expansion itself (and the resulting expansion of CUG in the mRNA) is thought to underlie an RNA-mediated pathogenesis.

What is the mechanism by which large tracts of the CUG trinucleotide, in the noncoding regions of genes, lead to the DM1 and DM2 phenotypes? The pathogene sis appears to result from the binding of the CUG repeats to RNA-binding proteins. Consequently, the pleiotropy that typifies the disease may reflect the broad array of RNA-binding proteins to which the CUG repeats bind. Many of the RNA-binding proteins sequestered by the excessive number of CUG repeats are regulators of splicing. Indeed, more than a dozen distinct pre-mRNAs have splicing alterations in patients with DM1, including cardiac troponin T (which might account for the cardiac abnormalities) and the insulin receptor (which may explain the insulin resistance). Thus the myotonic dystrophies are referred to as spliceopathies. Knowledge of the abnormal processes underlying DM1 and DM2 is incomplete, but these molecular insights offer hope that a rational small molecule therapy might be developed.

Class 3: Diseases Due to Repeat Expansion of a Codon That Confers Novel Properties on the Affected Protein

Huntington Disease. Huntington disease is an autosomal dominant neurodegenerative disorder associated with chorea, athetosis (uncontrolled writhing movements of the extremities), loss of cognition, and psychiatric abnormalities (Case 24). The pathologic process is caused by the expansion – to more than 40 repeats – of a CAG codon in the HTT gene, resulting in long polyglutamine tracts in the protein, huntingtin. Evidence suggests that the proteins with expanded poly glutamine sequences have novel properties: the expanded tract confers novel features on the protein that damage specific populations of neurons and produce neuro degeneration by unique toxic mechanisms. The most striking cellular hallmark of the disease is the presence of insoluble aggregates of the abnormal protein (as well as other polypeptides) clustered in nuclear inclusions in neurons. The aggregates are thought to result from nor mal cellular responses to the misfolding of huntingtin that results from the polyglutamine expansion. Dramatic as these inclusions are, however, their formation may be protective rather than pathogenic.

There is no unifying model of the neuronal death mediated by polyglutamine expansion in huntingtin. Many cellular processes are disrupted by expanded huntingtin in its soluble or aggregated form, including transcription, vesicular transport, mitochondrial fission, and synaptic transmission and plasticity. Ultimately, the most critical and primary events in the pathogenesis will be identified, perhaps guided by genetic analyses, leading to correction of the phenotype. For example, expanded huntingtin associates abnormally with a mitochondrial fission protein, GTPase dynamin-related protein 1 (DRP1), leading to multiple mitochondrial abnormalities in individuals with Huntington disease. Remarkably, in mice, these defects are rescued by reducing DRP1 GTPase activity, suggesting both that DRP1 may be a therapeutic target for the disorder and that mitochondrial abnormalities play important roles in Huntington disease.

Despite the substantial progress in identifying novel repeat expansions and our understanding of the molecular events that underlie the pathology of the unstable repeat expansion diseases, we are only beginning to dissect the genetic and pathogenic complexity of these important conditions. It is clear that the use of new genomic technologies and study of animal models are providing critical insights into these disorders. Such insights should soon lead to interventions to prevent or to reverse the pathogenesis of these slowly developing disorders. We begin to explore the concepts relevant to the treatment of disease in the next chapter.

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العتبة العباسية المقدسة تعلن أسماء الفائزين بمسابقة الذكرى الميمونة لولادة الإمام الحسين (عليه السلام)

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المزيد

الآخبار الصحية

عرض شائع على الأصابع.. قد يكشف سرطان الرئة مبكرا

7 مشروبات طبيعية لتقليل التوتر والقلق

دراسة: "خطر مبكر" يهدد صحة الأطفال

الجوز أو الفول السوداني.. أيهما يتفوّق في حماية القلب؟

المزيد

الآخبار التكنلوجية

مفاجأة علمية عن الإنجاب.. كم طفلا يطيل عمر المرأة؟

استطلاع يكشف "الأكثر قلقا" من تأثر الوظائف بالذكاء الاصطناعي

هل يمنحك تناول الجزر يوميا سمرة طبيعية؟

إنجاز طبي تاريخي.. جراحة قلب بلا شق في الصدر

المزيد

مواضيع ذات صلة

The Current State of Treatment of Genetic Disease

Normal Collagen Structure and Its Relationship to Osteogenesis Imperfecta

Cystic Fibrosis

Familial Hypercholesterolemia: A Genetic Hyperlipidemia

A Loss of Glycosylation: Mucolipidosis II or I-Cell Disease

Congenital Disorders of Glycosylation

The Example of Diseases Related to the X Chromosome: Hemophilia A and B

The Example of an Autosomal Recessive Disease: Cystic Fibrosis

Hemoglobin E: A Structurally Altered Hemoglobin With Thalassemia Phenotypes

The β- Thalassemias

The α- Thalassemias

Hemoglobin Structural Alterations