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Brain. 2014 May;137(Pt 5):1282-303. doi: 10.1093/brain/awt202. Epub 2013 Aug 22.

Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder.

Author information

1
1 Departments of Neurology, Human Genetics and Paediatrics; Emory University, Atlanta GA, USA.

Abstract

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.

KEYWORDS:

Lesch-Nyhan disease; genotype–phenotype correlations; neurogenetics

PMID:
23975452
PMCID:
PMC3999711
DOI:
10.1093/brain/awt202
[Indexed for MEDLINE]
Free PMC Article

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