IDUA mutational profiling of a cohort of 102 European patients with mucopolysaccharidosis type I: identification and characterization of 35 novel α-L-iduronidase (IDUA) alleles

Abstract

Mutational analysis of the IDUA gene was performed in a cohort of 102 European patients with mucopolysaccharidosis type I. A total of 54 distinct mutant IDUA alleles were identified, 34 of which were novel including 12 missense mutations, 2 nonsense mutations, 12 splicing mutations, 5 micro-deletions, 1 micro-duplication 1 translational initiation site mutation, and 1 'no-stop' change (p.X654RextX62). Evidence for the pathological significance of all novel mutations identified was sought by means of a range of methodological approaches, including the assessment of evolutionary conservation, RT-PCR/in vitro splicing analysis, MutPred analysis and visual inspection of the 3D-model of the IDUA protein. Taken together, these data not only demonstrate the remarkable mutational heterogeneity characterizing type 1 mucopolysaccharidosis but also illustrate our increasing ability to make deductions pertaining to the genotype-phenotype relationship in disorders manifesting a high degree of allelic heterogeneity.

Evaluation and identification of IDUA gene mutations in Turkishpatients with mucopolysaccharidosis type I

“…Interestingly, this mutation was reported as being specific to Turkey (allele frequency, (20). p.P533L is a rare mutation reported only in Russian patients as a compound heterozygous state (14).We detected the same mutation in one of the screened patients in a homozygous fashion.…”

“…In addition, p.M1L leads to a loss of the signal peptide sequence of the protein, which results in the disruption of the transport process into the endoplasmic reticulum and lysosomes (19). This mutation has already been reported in Chinese and Spanish (19,20) patients.…”

“…Up until now, 37 different nonpathogenic variations have been described (20). No clear information is available regarding their effect on enzyme activity or stability in MPS-I patients.…”

Experiences of parents and patients with the timing of Mucopolysaccharidosis type I (MPS I) diagnoses and its relevance to the ethical debate on newborn screening

“…Although second-tier screening by genotyping will allow the phenotype to be predicted in a number of patients [36,37], phenotypic classification at diagnosis will not be feasible in a significant number of cases. Adding MPS I to NBS programs may therefore result in parental anxiety over the uncertain phenotype and optimal treatment strategy.…”

Mucopolysaccharidosis (MPS) Physical Symptom Score: Development, Reliability, and Validity

“…These physical signs and symptoms together with increased urinary excretion of GAG (glycosaminoglycan), and absent or deficient alpha-L-iduronidase enzyme activity are observed in all forms of MPS I (Terlato and Cox 2003;Scott et al 1995;Beesley et al 2001), but no method exists to accurately summarize phenotypic disease burden in retrospective or prospective research studies. Genotype-phenotype correlations have been established to a limited degree in Hurler syndrome and even more limited in the attenuated forms (Pastores et al 2007;Terlato and Cox 2003;Scott et al 1995;Beesley et al 2001;Bertola et al 2011;Ahmed et al 2014a). Standard of care treatments such as hematopoietic cell transplant (HCT) (Peters et al 1996;Peters et al 1998;Souillet et al 2003;Staba et al 2004) in Hurler syndrome and enzyme replacement therapy (ERT) (Kakkis et al 2001;Wraith et al 2004) for the attenuated syndromes ameliorate some but not all symptoms.…”