Mechanisms for phenotypic variation in Lesch–Nyhan disease and its variants

Abstract

Lesch–Nyhan disease is a neurogenetic disorder caused by mutation of the HPRT1 gene on the X chromosome. There is significant variation in the clinical phenotype, with more than 300 different known mutations. There are few studies that have addressed whether similar mutations result in similar phenotypes across different patients because hypoxanthine–guanine phosphoribosyltransferase (HGprt) deficiency is rare, and most mutations are unique or limited to individual families. However, recent studies have revealed multiple unrelated patients with similar mutations, providing an opportunity to examine genotype–phenotype correlations. We found significant variation among the clinical features of 10 patients from 8 unrelated families all carrying a mutation replacing guanine with adenine at base position 143 (c.143G>A) in the HPRT1 gene. This mutation results in replacement of arginine by histidine at amino acid position 48 (p.arg48his) in the HGprt enzyme. Biochemically, the enzyme exhibits reduced thermal integrity, a mechanism that may explain clinical variation. The literature reveals similar clinical variation among other patients with similar mutations, although the variation is relatively minor across the whole population of patients. Identifiable sources of clinical variation include known limitations of clinical ascertainment and mechanisms that affect residual enzyme activity and stability. These results are helpful for understanding genotype–phenotype correlations and discordance and likely are applicable to other neurogenetic disorders where similar variation occurs.

Late diagnosis of Lesch-Nyhan disease variant

“…The enzyme activity <1.5% results in Lesch-Nyhan syndrome which includes hyperuricaemia, cognitive impairment, neurological dysfunction and behavioural deficits 4 5. Residual enzyme function between 1.5% and 8% results in LND variants.…”

Genotype-Phenotype Correlations in Lesch-Nyhan Disease

“…Furthermore, an unstable mutant might cause varied clinical phenotypes in different patients, as in vivo stability could be influenced by age, health, and other variables. In fact, variable residual enzyme activity due to protein instability has been proposed to underlie the varied phenotypes associated with R48H, which has been associated with both HND and HRH (20).…”

“…Expression Vector-The construction of the cDNA clone encoding full-length human HGprt has been reported previously (20). PCR primers were designed to add the MGHHHH-HHQGGCCPGCCGG sequence to the N terminus, in which a tag containing six histidine residues facilitated protein purification.…”

Multidisciplinary Assessment and Treatment of Self-Injurious Behavior in Autism Spectrum Disorder and Intellectual Disability: Integration of Psychological and Biological Theory and Approach

“…In LNS, a mutation of q26.2-q26.3 on the X chromosome results in a defect in the enzyme hypoxanthineguanine-phosphoribosyl-transferase (HPRT) (Sampat et al 2011). The resulting dysfunction in purine metabolism leads to an overproduction of purine 5 and the accumulation of uric acid.…”