9789 Mled Genet 1993; 30: 978-981 REVIEW ARTICLE J Med Genet: first published as 10.1136/jmg.30.12.978 on 1 December 1993. Downloaded from Dynamic mutations on the move Grant R Sutherland, Robert I Richards It is only a short time since the isolation and quences is rapidly increasing (table). These characterisation of the fragile X syndrome mu- include another fragile site (FRAXE) that may tation'-3 uncovered a new genetic element and be associated with mild mental retardation.'2 mechanism of mutation. The genetic element This fragile site has turned out to be similar in was an unstable DNA sequence resulting from structure to the fragile X (FRAXA), involving amplification of a naturally occurring poly- the same trinucleotide p(CCG)n and being morphic trinucleotide repeat, p(CCG)n. The close to a CpG island which is hypermethy- mechanism of mutation, which we have lated when the copy number exceeds approx- termed dynamic mutation,4 is the change (in- imately 200.* crease or decrease) in copy number of the The dynamic mutations characterised to trinucleotide repeat with the rate of change date fall into two categories probably deter- related to the number of copies present at any mined by whether the trinucleotide repeat is in time. This process, in which an initial change a translated or untranslated region of a gene. to a DNA sequence alters the chance of further The mutations in known or presumed changes to it, contrasts with classical or static untranslated regions, FRAXA, FRAXE, and mutation in which the product of a mutation is DM, appear to have little constraint on the no more likely to undergo further changes than number of repeats, which can range up to was the initial DNA sequence. several thousand copies. When the mutation is The instability of the amplified p(CCG)n in a presumptively translated region of the repeat in fragile X syndrome is such that gene (SBMA, HD, SCAI) the amplification is different cells in different tissues, and even restrained and rarely exceeds 100 copies of the different cells in the same tissue, can have repeat. The molecular basis for this limit will different numbers of copies of the repeat. Fur- hopefully become clearer after more detailed thermore, when the repeat is transmitted from analysis of the biology of the respective parent to offspring the number of copies can encoded proteins. http://jmg.bmj.com/ change markedly. Hence different subjects in a When compared to other types of single single family who carry the mutation can have gene defect the properties of dynamic muta- it in different forms. Normal X chromosomes tion diseases afford distinct advantages and have six to about 50 copies of the repeat. The disadvantages for diagnosis. The mutations mutation appears to begin as a small increase seen in most single gene defects are character- in copy number out of the normal range. This istically variable and numerous, occasionally a is transmitted unstably over a few generations, single mutation may predominate (as does gradually increasing when transmitted by AF508 in cystic fibrosis), but it still remains on October 1, 2021 by guest. Protected copyright. women but with little change in size when one of many at that locus. The dynamic muta- transmitted by males. Subjects with small size tion disorders are remarkably homogeneous. increases (up to about 200 copies) are clinically Apart from fragile X syndrome where a few normal and said to carry premutations at this deletions and a point mutation in the gene locus. (FMR1) have been described, no other muta- The properties of this new genetic element tions in the genes involved in dynamic muta- provided possible mechanisms for a variety of tion disorders have been recorded. This is a phenomena which were poorly understood.' great advantage for the diagnostic laboratory These included incomplete penetrance, vari- where the primary diagnosis of these disorders able expression, other fragile sites, and anti- can now be made with confidence. The major cipation. The prediction that anticipation, es- pecially as shown by myotonic dystrophy *Xoienc/lature. 'I'here arc only 10 possiblc diffcrcnt trinucle,o- tides which can be produced from the four primary bases from Centre for Medical (DM), was the result of an unstable sequence which DNA is constructed. Only two of thcse have becn In this disease the tri- identified in dynamic mutations and thesc are p(CCG)n and Genetics, Department was soon confirmed.`-5 because of Cytogenetics and nucleotide was p(AGC)n. This finding of a p(AGC)n. Confusion is rampant in published reports Molecular Genetics, there is no consistent nomenclature for these sequences. TIhe dynamic mutation in DM allowed the recogni- p(CCG)n rcpcat associatcd wvith fragile sites on the X chromo- Women's and some has bccn cxpresscd as p(CGG)n, p(C CG)n, and Children's Hospital, tion that anticipation was a legitimate clinical p(GCC)n. The convention proposed bv the gene mapping Adelaide, SA 5006, observation,9"" now with an acceptable genetic w,vorkshops for polymorphic oligonucleotidc rcpeats is that the Australia. bases be written in alphabctical order from 5' to 3, thus G R Sutherland mechanism, and not an artefact resulting from p(AGC)n and not p(CTG)n for the DM repcat. We arc of the R I Richards biased ascertainment." Vicw that adhering to this convention will make the body of publications much more intclligible to those readers who wish The number of disorders resulting from not intimatelv Correspondence to to follow this area of genctics but wsho are Dr Sutherland. unstable amplification of trinucleotide se- involved with it. Dynamic mutations on the move 979 disadvantages relate to uncertainty over the increase when it is transmitted by either par- relationship between genotype and phenotype. ent, but once males have about 600 to 700 Somatic variation can mean that copy number, copies little further increase occurs and de- determined from peripheral blood lympho- creases in size are seen. Females can, however, J Med Genet: first published as 10.1136/jmg.30.12.978 on 1 December 1993. Downloaded from cytes, is not an accurate determination of the have children with up to approximately 4000 size of the repeat in the affected tissue(s). In copies of the repeat. Studies on sperm from addition (perhaps as a consequence) there can DM males are yet to be reported. be overlap in copy number for the different The basis for the sex differences, including phenotypic categories (table). For example, in the imprinting associated with the fragile X, HD there is a very small area of overlap in the are unknown. Whether they reflect the dif- copy number distributions of normal and mu- ferences in the mechanisms of gamete forma- tant chromosomes. About 2% of mutant chro- tion or some other property of the sequences mosomes have copy numbers at the top of the themselves remains unclear. There is evidence normal range.'3 In practice, the vast majority in fragile X syndrome that the increases in of direct diagnoses of dynamic mutation dis- repeat copy number occur early in develop- eases based upon repeat copy number are ment after which time the sequence is stabi- reliable. lised and copy number changes no longer Parent of origin effects are marked in trans- occur in somatic tissues. Jansen et al'8 reported mission of dynamic mutations. In fragile X findings that suggest imprinting does not con- syndrome the premutation only progresses to a tribute to the manifestation of DM. full mutation and becomes clinically signific- ant when it is transmitted by a female. In DM, the congenital form of the disease only occurs Effect of repeat copy number when a child receives the mutation from its In some of the dynamic mutation disorders mother. In HD, and possibly spinocerebellar there is a relationship between copy number ataxia, juvenile onset of the disease is pater- and age of onset of disease. This is most clearly nally determined. The instability of the re- seen in spinocerebellar ataxia where there is a peats would appear to be different in germline clear curvilinear relationship with only little and somatic tissues. In fragile X only small scatter.'9 In DM there is a general relationship changes, within the premutation range, are with the congenital form of the disease having apparently transmitted through sperm and the largest number of repeats, but for any possibly also through ova.'4 The large expan- given copy number there is a wide range of sions seen in somatic tissues occur postzygoti- ages of onset.202' A similar situation exists for cally but, by some imprinting mechanism, Huntington's disease; high copy numbers are these expansions only occur on the maternally associated with juvenile onset but there ap- transmitted chromosome. The p(AGC)n re- pears to be little relation between age of onset peat in HD sperm is particularly unstable and and copy number where there are fewer than may be the reason why there are greater dif- 50 repeats. Andrew et aP22 report that 50% of ferences in copy number between fathers and the variation in age of onset in Huntington's their chil- disease can be attributed to repeat copy their children than mothers and http://jmg.bmj.com/ dren. '5 number. In Kennedy disease there is general The parental bias of congenital DM trans- decreasing age of onset with increasing copy mission appears to be because of constraints on number.23 the size of the repeat which can be transmitted In fragile X, generally, when n exceeds by males; these constraints are not apparent in about 200, transcription of the FMR1 gene maternal transmission.'6 17 In particular, the stops (in lymphocytes), the p(CCG)n repeat copy number of the p(AGC)n repeat may and adjacent CpG island become hypermethy- on October 1, 2021 by guest.