Хромосомные мутации синоним

2 Chromosome Mutations

Different types of chromosome mutations can originate in the germinal cells. Nonreduction of the whole chromosome set will lead to polyploid gametes, and nondisjunction of single chromosomes leads to aneuploidy and chromosome breakage to structural chromosome aberrations. These three types of events have probably different mechanisms of origin. Therefore, the assumption seems likely that a given agent will mainly induce only one of these types of mutations.

The difficulties involved in a cytogenetic screening program of newborns and spontaneous abortions are both of practical and theoretical nature. The practical problems are mainly concerned with the collection of material and with the costs, while the theoretical problems concern the interpretation of the incidence figures. The practical difficulties can be overcome, but the interpretation of the incidence figures requires some further comments. It is well known that maternal age at conception is of etiological importance for several of the chromosome abnormalities. An unchanged incidence of children with chromosome aberrations might therefore be due to a balance between, for instance, a decreasing maternal age on one hand and an increased chromosome mutation frequency on the other. Furthermore, incidence variations with season and socioeconomic class have been reported (Nielsen and Friedrich, 1969; Robinson et al., 1969), and all these factors have to be taken into consideration in evaluation of the data.

Thus, a number of problems are involved in the estimation of changes in both the gene and chromosome mutation frequencies in germinal cells. Even if these problems can be overcome, the question of what might have caused a registered change in the mutation frequency remains to be elucidated. This might turn out to be an almost unsolvable problem, even if retrospective studies sometimes might give hints with regard to the etiological factor (s) involved.

2 DYT6 Dystonia

DYT6 maps to chromosome 8p and mutations are inherited in an autosomal dominant pattern with reduced penetrance (Almasy et al., 1997). The gene for DYT6, THAP1, was first identified in Amish Mennonite families (Fuchs et al., 2009), whose causative mutation is a 5-base pair (GGGTT) insertion followed by a 3-base pair deletion (AAC) (c.135_139delinsGGGTTTA) in exon 2. This mutation results in a frame shift at amino acid 44 and a premature stop codon at position 73. THAP1 mutations as a cause of PTD were initially thought to be restricted to related Amish Mennonite families, but different THAP1 mutations in families with diverse ancestries have now been identified (Bonetti et al., 2009; Bressman et al., 2009; Djarmati et al., 2009; Houlden et al., 2010; Schneider et al., 2009). In a clinically restricted group of non-DYT1 families with early-onset nonfocal PTD, 25% were found to have a THAP1 mutation (Bressman et al., 2009; Djarmati et al., 2009; Schneider et al., 2009). However, only 4.5% of a Dutch dystonia cohort with early-onset PTD and 2.5% of a British dystonia cohort with a variety of phenotypes were found to have THAP1 mutations (Groen et al., 2010; Ritz et al., 2010). In addition to generalized dystonia, a small number of adult-onset focal cervical and laryngeal dystonia patients were found to have THAP1 single base-pair substitutions (Xiao et al., 2010).

Despite the diversity of mutations and ancestries, there is phenotypic similarity among cases. DYT6 dystonia usually begins in an arm, the neck, or other cranial muscles with two thirds eventually having involvement of the cranial muscles and impairment of speech. Symptom onset is typically early, but a significant proportion has symptoms begin after age 18 years.

THAP1 contains a highly conserved THAP domain at the N-terminus and a nuclear localization domain at its C-terminus. THAP domains are atypical zinc fingers responsible for sequence-specific DNA binding, and THAP1 regulates many proteins involved in endothelial cell proliferation (Cayrol et al., 2007). Two recent studies demonstrated that THAP1 also interacts with the TOR1A promoter region. Thus, THAP1 mutations may lead to dystonia by transcriptional dysregulation of TOR1A. This interaction suggests that DYT1 and DYT6 dystonia share a common pathogenetic pathway (Gavarini et al., 2010; Kaiser et al., 2010).

C. The cubitus interruptus gene and the “Dubinin” effect

Dubinin and Sidorov (1934a, 1934b) described a genetic phenomenon involving the fourth chromosome mutation cubitus interruptus (ci). This is sometimes called the “Dubinin” effect (Lewis, 1950). Dubinin and Sidorov crossed 19 translocations involving the fourth chromosome to the recessive ci mutation. Ten of these translocations failed to completely complement the ci mutation, that is, the ci mutation behaved as a dominant when heterozygous to the translocations. Dubinin (1935) and Sturtevant and Dobzhansky (Dobzhansky, 1936) tested another 29 translocations, of which 12 also failed to complement the ci mutation. Flies homozygous for some of these translocations could be recovered; the homozygotes did not have a ci mutant phenotype, suggesting that the ci gene was not mutated on the translocation chromosomes (Dubinin and Sidorov, 1934b). Several of the translocations were also examined in haplo-IV flies that had only the translocated fourth chromosome (the fourth chromosome is small enough that these aneuploids survive). Again, if the ci gene in the translocated chromosome were altered, these flies were expected to have the ci mutant phenotype; they did not (Dubinin and Sidorov, 1934b). Sidorov (1941) and Stern and Heidenthal (1944) irradiated chromosomes carrying the ci mutation and recovered translocations carrying the ci mutation in cis. Many of these translocations behaved as though they now carried a dominant ci mutation, i.e., flies heterozygous for a translocation often had a ci mutant phenotype, even though they carried a wild-type ci allele on the normal fourth chromosome. The recessive ci mutation became dominant when the fourth chromosome carrying it was involved in a translocation. Although Ephrussi and Sutton (1944) pointed out that these results suggested a role for chromosome pairing in the phenomenon, the effects of translocations on ci expression continued to be primarily cited as an example of a position effect. Although studied extensively by Stern and his colleagues (Stern and Heidenthal, 1944; Stern et al., 1946a, 1946b; Stern and Kodani, 1955), a simple model to explain the results remained elusive.

A simple explanation for the Dubinin effect was finally proposed by Locke and Tartof (1994). They proposed that the recessive ci mutation is not a loss-of-function mutation, but causes misexpression of the ci gene due to loss or inactivation of a negative cis-regulatory element. When able to pair with a wildtype ci gene, the negative cis-regulatory element in the wild-type gene can repress the mutant ci gene in trans. Disruption of pairing in translocation heterozygotes (which should be independent of whether the ci mutation is carried by the wildtype or translocated chromosome) prevents the negative cis-regulatory element of the wild-type gene from repressing in trans. The ci mutant gene is derepressed, causing the ci mutant phenotype. Molecular and developmental analyses support this model. The ci phenotype of recessive ci mutations does appear to result from derepression of the ci gene (Schwartz et al., 1995; Slusarski et al., 1995). Recessive ci mutations map to a region upstream of the ci transcription unit that includes a cis-regulatory element that can repress a reporter gene in a transgenic assay (Locke and Tartof, 1994; Schwartz et al., 1995; Slusarski et al., 1995).

Other X-Linked ID Conditions

The increased prevalence of ID in males and the relative ease of detecting familial transmission of X-chromosome mutations have led to the discovery of novel ID genes on the X chromosome. Since the early 1990s, more than 120 genes have been identified as causes of X-chromosome-linked syndromic and nonsyndromic ID (Table 51-4).

Mechanistically some of these genes work directly at the level of the synapse. For example, the protein family neuroligin on the postsynaptic membrane (with two X-linked neuroligin genes [NLGN3 and NLGN4]), and its binding partner neurexin on the presynaptic side have been shown to promote synapse formation in vitro. Similarly, multiple genes that participate in signaling at the synapse through the small G protein RHO are mutated in many cases of X-linked ID: GDI1, PAK3, OPHN1, and ARHGEF6. There are also many genes without synaptic function that are well-established causes of ID, such as the genes ARX and MECP2. These genes can cause syndromic ID (as in patients with X-linked lissencephaly with ambiguous genitalia [XLAG] and Rett’s syndrome) and nonsyndromic ID, depending on the severity of the mutation. These observations demonstrate the complexity of understanding how genetic alteration causes mental retardation, what form it takes, and how genotype may correlate with phenotype.

Continuity of Genetic Traits

In a comprehensive genetic assessment of 12,127 contemporary male individuals representing 163 East Asian populations, three Y chromosome mutations (YAP+, M89T, and M130T) were associated with a fourth mutation M168T, which originated in Africa approximately 35–89 kya. In this study, no input from East Asia was detected and the dispersal eastward points to a relative recent migration. These results are congruent with a recent out of Africa migration.⁸⁴ Yet, not all the genetic data available is consistent with a recent out of Africa migration of AMHs giving rise to all human populations worldwide. For example, in a study of 15 DNA sequences on the X chromosome, it was found that the DNA sites date back to various times and not a single time as expected by the single origin theory. Some of these DNA sites date back to about 2.0 mya when erectus originated in Africa.⁸⁵ These results also suggest that a population separation occurred at the time of erectus and not a recent split of sapiens as predicted by the Out of Africa theory. Furthermore, some of the DNA sequences exhibit more diversity in Asia, not in Africa as expected by the Out of Africa model. Greater variability is generally considered diagnostic of regions of origin because diversity is generated as a function of time; older locations possess more diversity.

A number of other sites distributed throughout the sapiens DNA also indicate inconsistencies with the notion that AMHs recently and uniquely originated in Africa in the absence of introgression. These studies point to old separation times of human populations dating to the origins of erectus in Africa.⁸⁶ Included among these deep-rooted diagnostic DNA locations are a ribonucleotide reductase (RRM2) gene, the microtubule-associated protein tau (MAPT) gene, an acetylneuraminic acid hydroxylase (CMP-N) gene, and a pyruvate dehydrogenase (PDHA1) gene. All of these studies are contradictory to the seminal mtDNA data that support a recent single Out of Africa dispersal. In addition, the notion of a recent single dispersion Out of Africa was challenged when 34 unique migration events involving Africa and Eurasia were detected by statistical analyses of genes. Nineteen of the thirty-four DNA sequences indicated that the gene flow occurred approximately 1.46 mya, three are correlated with the erectus migration out of Africa about 2.0 mya, only five were related to a recent expansion Out of Africa, and seven took place at intermediate time periods. In this study, the single migration from Africa with replacement was soundly negated with greater than 99% confidence.⁸⁷

Genetic Diversity

Genetic diversity is reliant on the heritable variation within and between populations of organisms. New genetic variation arises in individuals by gene and chromosome mutations, and in organisms with sexual reproduction it can be spread through the population by recombination. It has been estimated that in humans and fruit flies alike, the number of possible combinations of different forms of each gene sequence exceeds the number of atoms in the universe. Other kinds of genetic diversity can be identified at all levels of organization, including the amount of DNA per cell and chromosome structure and number. Selection acts on this pool of genetic variation present within an interbreeding population. Differential survival results in changes of the frequency of genes within this pool, and this is equivalent to population evolution. Genetic variation enables both natural evolutionary change and artificial selective breeding to occur (Thomas, 1992).

Only a small fraction (<1%) of the genetic material of higher organisms is outwardly expressed in the form and function of the organism; the purpose of the remaining DNA and the significance of any variation within it are unclear (Thomas, 1992). Each of the estimated 109 different genes distributed across the world’s biota does not make an identical contribution to overall genetic diversity. In particular, those genes that control fundamental biochemical processes are strongly conserved across different taxa and generally show little variation, although such variation that does exist may exert a strong effect on the viability of the organism; the converse is true of other genes. A large amount of molecular variation in the mammalian immune system, for example, is possible on the basis of a small number of inherited genes (Thomas, 1992).

Phenylketonuria

Classic phenylketonuria (PKU) is caused by near-complete deficiency of phenylalanine hydroxylase activity leading to hyperphenylalaninemia. The phenylalanine hydroxylase gene, PAH, is located in chromosome 12 and mutations in PAH are inherited in an autosomal recessive fashion. PKU was the first metabolic cause of mental retardation to be identified and is routinely screened for in all newborns.^40,41 It is also an example of a disorder fully treatable by dietary restriction. A small proportion of infants with hyperphenylalaninemia have an underlying impaired synthesis or recycling of tetrahydrobiopterin (BH4) in the presence of a normal PAH gene, a condition that is independently treatable.⁴² Classic untreated PKU leads to microcephaly, epilepsy, and severe intellectual and behavioral disabilities. The excretion of excessive phenylalanine and its metabolites can confer a musty odor to the skin, and the associated inhibition of tyrosinase causes decreased skin and hair pigmentation. Patients also exhibit decreased myelin formation and deficient production of dopamine, norepinephrine, and serotonin. Motor disability can be prominent later in life. Untreated maternal PKU can produce congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and mental retardation in the offspring. The diagnosis is based on plasma phenylalanine measurement and DNA sequence analysis. Prenatal diagnosis using amniocytes is available. PKU treatment consists of dietary restriction of phenylalanine.⁴³ A fraction of patients with primary phenylalanine hydroxylase deficiency respond to the 6R-BH4 isomer, which may act by enhancing residual enzyme function.⁴⁴

IX. Phenylketonuria

PKU was the first metabolic cause of mental retardation to be identified and is routinely screened for in all newborns. It is also an example of a disorder fully treatable by dietary restriction. A small proportion of infants with hyperphenylalaninemia display impaired synthesis or recycling of tetrahydrobiopterin (BH4) in the presence of a normal PAH gene, a condition that is independently treatable (Blau & Erlandsen, 2004). Classical untreated PKU leads to microcephaly, epilepsy, and severe intellectual and behavioral disabilities. The excretion of excessive phenylalanine and its metabolites can confer a musty odor to the skin, and the associated inhibition of tyrosinase causes decreased skin and hair pigmentation. Patients also exhibit decreased myelin formation and deficient production of dopamine, norepinephrine, and serotonin. Motor disability can be prominent later in life. Untreated maternal PKU can produce congenital heart disease, intrauterine and postnatal growth retardation, microcephaly, and mental retardation in the offspring. The diagnosis is based on plasma phenylalanine measurement and DNA sequence analysis. Prenatal diagnosis using amniocytes is available. PKU treatment consists of dietary restriction of phenylalanine. A fraction of patients with primary phenylalanine hydroxylase deficiency respond to BH4, which may act by enhancing residual enzyme function (Blau & Scriver, 2004). It is believed that the BH4 responsive form of PKU is caused by mutations that affect the enzyme Km by altering the binding affinity of BH4.

MOLECULAR BIOLOGY

During transformation to anaplastic forms, in addition to losses on chromosomes 1p and 19q, oligodendrogliomas accumulate losses on chromosome 9p (including the CDKN2A region), losses on chromosome 10q, and mutations of the p53 gene.^119,120 LOH at 1p and 19q predicts a durable response to PCV or temozolomide therapy as well as prolonged survival. Even a partial oligodendroglial component in a mixed oligoastrocytoma improves the response to therapy as well as survival compared with pure astrocytomas.^135,137,138 Similarly, recent studies by Zlatescu¹⁴⁰ and Mueller¹⁴¹ and their respective colleagues demonstrate a molecular genetic dichotomy in the distribution of oligodendroglial tumors of the cerebral hemispheres. Extratemporal oligodendrogliomas and oligoastrocytomas are more likely to have LOH at 1p and 19q and a normal p53 than are tumors found in the temporal lobes.^140,141

Categories and Frequencies