The spectrum of inherited mutations causing HPRT deficiency: 75 new cases and a review of 196 previously reported cases

Sunyaev

Proc. Natl. Acad. Sci. U.S.A.

2002

286

358

We study fitness landscape in the space of protein sequences by relating sets of human pathogenic missense mutations in 32 proteins to amino acid substitutions that occurred in the course of evolution of these proteins. On average, Ϸ10% of deviations of a nonhuman protein from its human ortholog are compensated pathogenic deviations (CPDs), i.e., are caused by an amino acid substitution that, at this site, would be pathogenic to humans. Normal functioning of a CPD-containing protein must be caused by other, compensatory deviations of the nonhuman species from humans. Together, a CPD and the corresponding compensatory deviation form a Dobzhansky-Muller incompatibility that can be visualized as the corner on a fitness ridge. Thus, proteins evolve along fitness ridges which contain only Ϸ10 steps between successive corners. The fraction of CPDs among all deviations of a protein from its human ortholog does not increase with the evolutionary distance between the proteins, indicating that substitutions that carry evolving proteins around these corners occur in rapid succession, driven by positive selection. Data on fitness of interspecies hybrids suggest that the compensatory change that makes a CPD fit usually occurs within the same protein. Data on protein structures and on cooccurrence of amino acids at different sites of multiple orthologous proteins often make it possible to provisionally identify the substitution that compensates a particular CPD.E volution unfolds on a fitness landscape, a map that relates fitness to the genotype (1). Obviously, most of possible genotypes are always unfit, and some of rare fit genotypes must be arranged in continuous ridges (networks). This general paradigm can be applied, inter alia, to the evolution of proteins. ''If evolution . . . is to occur, functional proteins must form a continuous network which can be traversed by unit mutational steps without passing through non-functional intermediates'' (2). However, data on fitness landscapes are limited, because only a tiny fraction of all possible genotypes is actually available, and inferring fitness of currently nonexisting genotypes is difficult (3-6). Relating data on human pathogenic missense mutations, which represent unfit genotypes, to interspecies differences between homologous proteins, all of which must be fit, offers a novel opportunity to probe the fitness landscape in the space of proteins.Human pathogenic amino acid substitutions tend to occur at less variable sites of proteins (7). Thus, an amino acid that in a nonhuman protein is different from the amino acid at the homologous site of the human ortholog would probably be benign for humans if placed into this site. Still, exceptions to this rule have been described (8, 9).For example, the 53rd site of human ␣-synuclein is normally occupied by Ala, and Ala 3 Thr substitution at this site predisposes to Parkinson's disease. Nevertheless, healthy mice (and rats) carry Thr at the homologous site of their ␣-synucleins (8). We call such a situation a compensated pathog...

Section: Methodsmentioning

confidence: 99%

Dobzhansky–Muller incompatibilities in protein evolution

Sunyaev

Proc. Natl. Acad. Sci. U.S.A.

2002

286

358

“…At 20 months, the patient was unable to control his head or speak; he also showed swallowing and severe dystonic-dyskinetic movement disorder of the upper limbs with generalized hypertonia crisis towards opistotonus. LND is a rare X-linked recessive disorder [2] characterized by the progressive development of mental retardation, spasticity, choreo-athetosis, self-mutilation, and hyperuricemia [3,4], due to complete deficiency of the activity of HGPRT (OMIM 308000) [2]. However, partially HGPRTdeficient patients (OMIM 300323) present these symptoms with different degrees of intensity [5].…”

Section: Sirsmentioning

confidence: 99%

“…In these patients, orange crystals may be identified in diapers during the first weeks of life, but only rarely are they an early sign of the disease [3,4,6]. For example, Jinnah et al [7] reported only one patient in 40 with LND.…”

Section: Sirsmentioning

confidence: 99%

Orange-colored diapers as first sign of Lesch-Nyhan disease in an asymptomatic infant

Gasperini

Stagi²,

Gasperini

et al. 2010

Pediatr Nephrol

Sirs, We read with great interest the letter of Demirdas and Schröder [1] about the differential diagnosis in changed color of urine in infants.We have followed a 3-month-old male who was hospitalized for the presence of orange-colored diapers. He was born from unrelated parents after an uneventful pregnancy. High levels of uric acid were found in the plasma (11.7 mg/dl; normal values 1.7-5.8). Kidney ultrasound examination showed mild and diffuse increase of signal in cortical area with nephrolithiasis. Fundus oculi, electroencephalogram (EEG), and brain ultrasound were normal. Successively, the infant presented dystonic movements, mild axial hypotonia, and hypertonia of the legs with increased tendon reflexes and scissoring. The study of purine and pyrimidine metabolism by electrospray ionization tandem mass spectrometry (MS-MS) showed high levels of hypoxanthine (20.3 mmol/mol of creatinine; normal values 0.43-11.31). Enzymatic assay in red cells showed an absence of hypoxanthine-guanine phosphoribosyltransferase activity (HGPRT). Molecular analysis confirmed the diagnosis of Lesch-Nyhan disease (LND; OMIM 300322) in the patient and his mother as a carrier: a duplication of 8 nucleotides 89-96 (89_96dupAGGATTTG) in exon 2 of HPRT1 gene was found in chromosome X.Brain magnetic resonance imaging showed white matter atrophy of bilateral symmetric temporal-insular regions with respective enlargement of subarachnoid spaces with mild decreased concentration of NAA and Cho at spectroscopy. At 20 months, the patient was unable to control his head or speak; he also showed swallowing and severe dystonic-dyskinetic movement disorder of the upper limbs with generalized hypertonia crisis towards opistotonus.

“…The defective enzyme is encoded by the HPRT1 gene, and more than 615 mutations are known (Fu et al 2014;Jinnah et al 2004). There are several variants of the disease with different clinical severity (Jinnah et al 2000(Jinnah et al , 2010Puig et al 2001;Schretlen et al 2005). HPRT is expressed in all tissues with high levels found in many regions of the brain.…”

Section: Introductionmentioning

confidence: 99%

The Effect of S-Adenosylmethionine on Self-Mutilation in a Patient with Lesch–Nyhan Disease

et al. 2016

Background: Lesch-Nyhan disease (LND) is an Xchromosomal disorder of purine metabolism characterized by hyperuricemia, dystonia, and self-mutilation, leading to an extremely high burden of disease in affected patients and families. Although allopurinol therapy can control hyperuricemia, it has no effect on self-mutilation and neurological symptoms. Single reports describe a beneficial effect of Sadenosylmethionine (SAM) on the neurological symptoms, which motivated us to evaluate this alternative treatment.Methods: We performed a double-blind placebo-controlled trial to analyze the effects of SAM on self-mutilation attempts in a male patient affected by LND. The trial lasted for 282 days and comprised three alternating verum and placebo periods of 50 days each. The mother of the patient recorded attempts of self-mutilation during the entire trial.Results: While verum and placebo were both well tolerated, a total of 1,762 events of self-mutilation were recorded, of which 1,281 events were in the placebo period and 481 in the verum period. The daily mean of events was 8.6 with placebo and 4.5 with SAM corresponding to a 50 % decrease in selfmutilation events under SAM treatment (p < 0.05).Conclusion: The results of this double-blind placebocontrolled single-case trial suggest that SAM can have a beneficial effect on self-mutilation in patients with LND, possibly by replenishing the purine pool in affected brain cells.