In all cases, gene functions are altered by an expansion of the repeats, but the precise threshold at which premutations are converted to full mutations differs with each disorder.
Whereas the expansion in fragile X syndrome occurs during oogenesis, in other disorders such as Huntington disease, premutations are converted to full mutations during spermatogenesis.
The expansion may involve any part of the gene, and the range of possibilities can be divided into two broad categories: those that affect untranslated regions (as in fragile X syndrome) and those that affect coding regions (as in Huntington disease) (
Fig. 7.19 ). When mutations affect noncoding regions, there is “loss of function,” because protein synthesis is suppressed (e.g., FMRP). By contrast, mutations involving translated parts of the gene give rise to misfolded proteins (e.g., Huntington disease). Many of these so-called “toxic gain-offunction” mutations involve CAG repeats that encode polyglutamine tracts, and the resultant diseases are sometimes referred to as polyglutamine diseases, affecting primarily the nervous system. Accumulation of mis-folded proteins in aggregates within the cytoplasm is a common feature of such diseases.
Pathologicamplificationoftrinucleotiderepeatscausesloss-of-function(fragileXsyndrome)orgain-of-functionmutations(Huntingtondisease).Mostsuchmutationsproduceneurodegenerativedisorders.
FragileXsyndromeresultsfromlossofFMR1 genefunctionandischaracterizedbymentalretardation,macroorchidism,andabnormalfacialfeatures.
Inthenormalpopulation,thereareabout29CGGrepeatsintheFMR1 gene.Thegenomesofcarriermalesandfemalescontainpremutationswith52to200CGGrepeatsthatcanexpandto4000repeats(fullmutations)duringoogenesis.
Whenfullmutationsaretransmittedtoprogeny,fragileXsyndromeoccurs.
•FragileXtremor/ataxiaresultingfromexpressionofaFMR1 genebearingpremutationdevelopsinsomemalesandfemales.TheaccumulationofcorrespondingmRNAinthenucleusbindsandsequesterscertainproteinsthatareessentialfornormalneuronalfunctions
Mitochondria contain several genes that encode enzymes involved in oxidative phosphorylation. Inheritance of mitochondrial DNA differs from that of nuclear DNA in that the former is associated with maternal inheritance. The reason for this peculiarity is that ova contain the normal complement of mitochondria within their abundant cytoplasm, whereas spermatozoa contain few, if any, mitochondria. The mitochondrial DNA of the zygote is therefore derived entirely from the ovum. Thus, only mothers transmit mitochondrial genes to their offspring, both male and female.
Diseases caused by mutations in mitochondrial genes are rare. Because mitochondrial DNA encodes enzymes involved in oxidative phosphorylation, diseases caused by mutations in such genes affect organs most dependent on oxidative phosphorylation (CNS, skeletal muscle, cardiac muscle, liver, and kidney). Leber hereditary optic neuropathy is the prototypical disorder in this group. This neurodegenerative disease manifests as progressive bilateral loss of central vision that leads in due course to blindness.
DiseasesCausedbyAlterationsofImprintedRegions:Prader-WilliandAngelmanSyndromes