Risk of neurodegenerative diseases in children conceived by intracytoplasmic sperm injection?

Abstract

Excessive amplifications of the trinucleotide repeat (CAG)n in the translated part of a series of human genes have been associated with various neurodegenerative diseases: spinobulbar muscular atrophy (SBMA) or Kennedy's disease, 1 La Spada AR Wilson EM Lubahn DB Harding AE Fischbeck KH Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.. Nature. 1991; 352: 77-79 Crossref PubMed Scopus (2395) Google Scholar Huntington's disease, 2 Huntington's Disease Collaborative Research GroupA novel gene containing a trinucleotide repeat that is unstable on Huntington's disease chromosomes.. Cell. 1993; 72: 971-983 Summary Full Text PDF PubMed Scopus (6995) Google Scholar spinocerebellar ataxia type 1 (SCA1), 3 Orr HT Chung MY Banfi S et al. Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1.. Nat Genet. 1993; 4: 221-226 Crossref PubMed Scopus (1470) Google Scholar spinocerebellar ataxia type 3 (SCA3) or Machado-Joseph disease, 4 Kawaguchi Y Okamoto T Taniwaki M et al. CAG expansion in a novel gene for Machado-Joseph disease at chromosome 14q 32.1.. Nat Genet. 1994; 8: 221-227 Crossref PubMed Scopus (1545) Google Scholar spinocerebellar ataxia type 6 (SCA6), 5 Zhuchenko O Bailey J Bonnen P et al. Autosomal dominant cerebellat ataxia (SCA6) associated with small polyglutamine expansions in the alphal A-voltage-dependent calcium channel.. Nat Genet. 1997; 15: 62-69 Crossref PubMed Scopus (1424) Google Scholar spinocerebellar ataxia type 7 (SCA7), 6 David G Durr A Stevanin G et al. Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SC A7).. Hum Mol Genet. 1998; 7: 165-170 Crossref PubMed Scopus (232) Google Scholar and dentatorubral pallidoluysian atrophy (DRPLA) disease. 7 Koide R Ikeuchi T Onoder O et al. Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA).. Nat Genet. 1994; 6: 9-13 Crossref PubMed Scopus (1035) Google Scholar The trinucleotide repeat expansion in each of these diseases is associated with “anticipation”, which means that the age at which the disease becomes manifest declines with successive generations. This trend can be explained by the instability of abnormally expanded repeats, which causes them to increase in size by unequal crossing-over or single-strand slippage events during meiotic DNA replication in the male or female germ-line. These mutations are then passed on to the next generation. However, CAG repeats can remain stable in the same genes, although often with different numbers in each gene copy. 8 Andrew SE Goldberg YP Hayden MR Rethinking genotype and phenotype correlations in polyglutamine expansion disorders.. Hum Mol Genet. 1997; 6: 2005-2010 Crossref PubMed Scopus (120) Google Scholar Moreover, the (CAG)n-encoded aminoacid, polyglutamine, most probably functions as a polar zipper (ie, it links specific transcription factors bound to separate DNA segments), 9 Perutz ME Johnson T Suzuki M et al. Glutamine repeats as polar zippers: their possible role in inherited neurodegenerative diseases.. Proc Natl Acad Sd USA. 1994; 91: 5355-5358 Crossref PubMed Scopus (941) Google Scholar or fine-tunes the transcriptional activation process of downstream genes. 10 Gerber HP Seipel K Georgiev O et al. Transcriptional activation modulated by homopolymeric glutamine and pro line stretches.. Science. 1994; 263: 808-811 Crossref PubMed Scopus (520) Google Scholar Linkage between male infertility and trinucleotide repeat expansion in the androgen-receptor geneOur results indicate a relation between CAG repeat length in the androgen-receptor gene and the risk of defective spermatogenesis. With the use of intracytoplasmic sperm injection, this mutation could be inherited, possibly leading to an increase in male infertility in future generations. Should further elongation of the CAG repeat occur in these future generations, there is an added risk of increased severity of male infertility, and potentially an increased incidence of neurodegenerative disease. Full-Text PDF