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

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.

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

“…Therefore, there is much value in studying a rare disease that might ultimately shed light on more common disorders. LNS was the first neurogenetic disorder for which the responsible enzyme was identified (109)(110)(111). Close to the 50th anniversary of its first description in two siblings (109), we continue to learn much from HGprt-deficiency, an enzyme defect that substantially modifies brain anatomy (115)(116)(117) and cause the neurobehavioral syndrome observed in LNS and LNVs (109)(110)(111).…”

“…LNS was the first neurogenetic disorder for which the responsible enzyme was identified (109)(110)(111). Close to the 50th anniversary of its first description in two siblings (109), we continue to learn much from HGprt-deficiency, an enzyme defect that substantially modifies brain anatomy (115)(116)(117) and cause the neurobehavioral syndrome observed in LNS and LNVs (109)(110)(111). Finally, through a massive research effort over the last 2 decades, it has now become clear that APP and its fragments play diverse roles in development and cell growth, cell adhesion, intercellular communication, signal transduction, nuclear signaling and structural and functional plasticity.…”

“…LNV is characterized by the consequences of overproduction of uric acid and a variable spectrum of neurological manifestations, without the manifestations of self-injurious behavior (110,111). The etiology of LNS and LNV involves a mutation of the HPRT1 gene, which is on the long arm of the X chromosome (Xq26.1), and it contains nine exons and eight introns (110,111). Because the HPRT1 gene is on the X chromosome, males are affected and females in the families are at risk for being carriers of the mutation.…”

“…The type of mutation and its location in the HPRT1 gene is therefore an important factor for provoking disease (LNS or LNV), not only through its effect on residual HGprt enzyme activity but also through its effect on interactions between mutated HPRT 1 and APP genes. For the same type of mutation in the HPRT1 gene, the response to epigenetic modifications due to epistasis may be different from one patient to another and this could explain the manifestation of different clinical phenotypes from different patients and also from different affected family members (111,122,123). …”

Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency

“…Substitution of Arg417 by a Cys residue prevents this interaction, a disulfide bridge involving Cys117 of both monomers inducing the formation of an aberrant homodimer. Indeed, mutation causing protein structure alteration is often associated with more severe phenotypes (Fu et al 2014). Interestingly, besides the complex I deficiency, a partial defect in complex V was noticed in our patient, whereas other respiratory chain activities were normal.…”