Anna Lisa E. Montalvo

Bio: Anna Lisa E. Montalvo is an academic researcher from International Centre for Genetic Engineering and Biotechnology. The author has contributed to research in topics: Mutation & Missense mutation. The author has an hindex of 9, co-authored 9 publications receiving 341 citations.

Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.

Abstract: Glycogen storage disease type II (GSDII) is a recessively inherited disorder due to the deficiency of acid alpha-glucosidase (GAA) that results in impaired glycogen degradation and its accumulation in the lysosomes. We report here the complete molecular analysis of the GAA gene performed on 40 Italian patients with late onset GSDII. Twelve novel alleles have been identified: missense mutations were functionally characterized by enzyme activity and protein processing in a human GAA-deficient cell line while splicing mutations were studied by RT-PCR and in silico analysis. A complex allele was also identified carrying three different alterations in cis. The c.-32-13T > G was the most frequent mutation, present as compound heterozygote in 85% of the patients (allele frequency 42.3%), as described in other late onset GSDII Caucasian populations. Interestingly, the c.-32-13T > G was associated with the c.2237G > A (p.W746X) in nine of the 40 patients. Genotype-phenotype correlations are discussed with particular emphasis on the subgroup carrying the c.-32-13T > G/c.2237G > A genotype.

Molecular and functional characterization of eight novel GAA mutations in Italian infants with Pompe disease.

Abstract: We characterized 29 unrelated patients presenting with the severe form of Pompe disease (Glycogen Storage Disease Type II, acid maltase deficiency) and identified 26 pathogenic mutations divided over 28 different genotypes. Among the eight new mutations, five were exonic point mutations (c.572A>G, c.1124G>T, c.1202A>G, c.1564C>G and c.1796C>A) leading to codon changes (p.Y191C, p.R375L, p.Q401R, p.P522A and p.S599Y); two were intronic point mutations (c.-32-3C>A and c.1636+5G>C) affecting mRNA processing; one was a single base deletion (c.742delC) generating a truncated protein (p.L248PfsX20). A comprehensive evaluation, based on different methodological approaches, confirmed the detrimental effect of the eight mutations on the protein and its function. Structural alterations potentially induced by the five missense mutations were also predicted through visual inspection of the atomic model of the GAA protein, in terms of both function and spatial orientation of specific residues as well as disturbance generated by amino acid substitutions. Although the remarkable heterogeneity of the mutational spectrum in Pompe disease was already known, our data demonstrate and confirm the power of molecular and functional analysis in predicting the natural course of Pompe disease.

Splicing mutations in glycogen-storage disease type II: evaluation of the full spectrum of mutations and their relation to patients’ phenotypes

Abstract: Glycogen-storage disease type II is an autosomal recessive-inherited disorder due to the deficiency of acid α-glucosidase. A large number of mutations in the acid α-glucosidase gene have been described to date. Among them, ∼15% are variations that may affect mRNA splicing process. In this study, we have for the first time comprehensively reviewed the available information on splicing mutations of the acid α-glucosidase gene and we have evaluated their possible impact on the splicing process using different in silico approaches. Out of the 39 different GAA-sequence variations described, an in silico analysis using seven different programs showed that 97% of them are predicted to have an impact on the splicing process. Moreover, this analysis showed a quite good correlation between the impact of the mutation on the splicing process and the clinical phenotype. In addition, we have performed the functional characterization of three novel sequence variants found in Italian patients and still uncharacterized. Using a minigene system, we have confirmed their pathogenic nature. In conclusion, this study has shown that in silico analysis represents a useful tool to select mutations that affect the splicing process of the acid α-glucosidase gene and provides an updated picture of all this kind of mutations reported till now.

Identification and molecular characterization of six novel mutations in the UDP-N-acetylglucosamine-1-phosphotransferase gamma subunit (GNPTG) gene in patients with mucolipidosis III gamma.

Abstract: Mucolipidosis type III (MLIII) is an autosomal recessive disorder affecting lysosomal hydrolase trafficking. In a study of 10 patients from seven families with a clinical phenotype and enzymatic diagnosis of MLIII, six novel GNPTG gene mutations were identified. These included missense (p.T286M) and nonsense (p.W111X) mutations and a transition in the obligate AG-dinucleotide of the intron 8 acceptor splice site (c.610–2A>G). Three microdeletions were also identified, two of which (c.611delG and c.640_667del28) were located within the coding region whereas one (c.609+28_610-16del) was located entirely within intron 8. RT-PCR analysis of the c.610–2A>G transition demonstrated that the change altered splicing, leading to the production of two distinct aberrantly spliced forms, viz. the skipping of exon 9 (p.G204_K247del) or the retention of introns 8 and 9 (p.G204VfsX28). RT-PCR analysis, performed on a patient homozygous for the intronic deletion (c.609+28_610-16del), failed to detect any GNPTG RNA transcripts. To determine whether c.609+28_610-16del allele-derived transcripts were subject to nonsense-mediated mRNA decay (NMD), patient fibroblasts were incubated with the protein synthesis inhibitor anisomycin. An RT-PCR fragment retaining 43 bp of intron 8 was consistently detected suggesting that the 33-bp genomic deletion had elicited NMD. Quantitative real-time PCR and GNPTG western blot analysis confirmed that the homozygous microdeletion p.G204VfsX17 had elicited NMD resulting in failure to synthesize GNPTG protein. Analysis of the sequences surrounding the microdeletion breakpoints revealed either intrinsic repetitivity of the deleted region or short direct repeats adjacent to the breakpoint junctions. This is consistent with these repeats having mediated the microdeletions via replication slippage and supports the view that the mutational spectrum of the GNPTG gene is strongly influenced by the properties of the local DNA sequence environment.

Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles.

Abstract: Tay-Sachs disease (TSD) is a recessively inherited disorder caused by the hexosaminidase A deficiency. We report the molecular characterization performed on 31 Italian patients, 22 with the infantile, acute form of TSD and nine patients with the subacute juvenile form, biochemically classified as B1 Variant. Of the 29 different alleles identified, fourteen were due to 15 novel mutations, two being in-cis on a new complex allele. The new alleles caused four frameshifts, three premature stop codons, three amino acid changes, two amino acid deletions and two splicing alterations. As previously reported, the c.533G>A (p.R178H) mutation was present either in homozygosity or as compound heterozygote, in all the patients with the late onset TSD form (B1 Variant); the allele frequency in this group is discussed by comparison with that found in infantile TSD. © 2005 Wiley-Liss, Inc.

2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.

Abstract: Writing committee me tions to which their s ply; see Appendix ACCF/AHATask Fo Surgeons Representa tative Heart Rhythm ography and Int Echocardiography Re ciety of America Rep resentative kkACCF/ Task Force member d This document was app Board of Trustees and ordinating Committee gery, American Soc Cardiology, Heart Fa for Cardiovascular A geons approved the d The American Associat as follows: Gersh BJ Naidu SS, Nishimura Bernard J Gersh, MB, ChB, DPhil, FACC, FAHA, Co-Chair* Barry J Maron, MD, FACC, CoChair* Robert O Bonow, MD, MACC, FAHA, Joseph A Dearani, MD, FACC,§,k Michael A Fifer, MD, FACC, FAHA,* Mark S Link, MD, FACC, FHRS,* Srihari S Naidu, MD, FACC, FSCAI,* Rick A Nishimura, MD, FACC, FAHA, Steve R Ommen, MD, FACC, FAHA, Harry Rakowski, MD, FACC, FASE,** Christine E Seidman, MD, FAHA, Jeffrey A Towbin, MD, FACC, FAHA, James E Udelson, MD, FACC, FASNC, and Clyde W Yancy, MD, FACC, FAHAkk

Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA).

Abstract: Gaucher disease (GD) is an autosomal recessive disorder caused by the deficiency of glucocerebrosidase, a lysosomal enzyme that catalyses the hydrolysis of the glycolipid glucocerebroside to ceramide and glucose. Lysosomal storage of the substrate in cells of the reticuloendothelial system leads to multisystemic manifestations, including involvement of the liver, spleen, bone marrow, lungs, and nervous system. Patients with GD have highly variable presentations and symptoms that, in many cases, do not correlate well with specific genotypes. Almost 300 unique mutations have been reported in the glucocerebrosidase gene (GBA), with a distribution that spans the gene. These include 203 missense mutations, 18 nonsense mutations, 36 small insertions or deletions that lead to either frameshifts or in-frame alterations, 14 splice junction mutations, and 13 complex alleles carrying two or more mutations in cis. Recombination events with a highly homologous pseudogene downstream of the GBA locus also have been identified, resulting from gene conversion, fusion, or duplication. In this review we discuss the spectrum of GBA mutations and their distribution in the patient population, evolutionary conservation, clinical presentations, and how they may affect the structure and function of glucocerebrosidase.

2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Executive Summary

Abstract: 2011;58;2703-2738; originally published online Nov 8, 2011; J. Am. Coll. Cardiol. W. Yancy Rakowski, Christine E. Seidman, Jeffrey A. Towbin, James E. Udelson, and Clyde Fifer, Mark S. Link, Srihari S. Naidu, Rick A. Nishimura, Steve R. Ommen, Harry Bernard J. Gersh, Barry J. Maron, Robert O. Bonow, Joseph A. Dearani, Michael A. Thoracic Surgeons Society for Cardiovascular Angiography and Interventions, and Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, of Thoracic Surgery, American Society of Echocardiography, American Society Developed in Collaboration With the American Association for Guidelines Cardiology Foundation/American Heart Association Task Force on Practice Cardiomyopathy: Executive Summary: A Report of the American College of 2011 ACCF/AHA Guideline for the Diagnosis and Treatment of Hypertrophic This information is current as of May 14, 2012 http://content.onlinejacc.org/cgi/content/full/58/25/2703 located on the World Wide Web at: The online version of this article, along with updated information and services, is