Prateek Gupta

FBN2 mutation associated with manifestations of Marfan syndrome and congenital contractural arachnodactyly

Congenital contractures involving multiple joints and a crumpled appearance of the helix of the ear are more common in CCA than MFS. Ectopia lentis is a complication present in approximately half of patients with MFS. The most common cardiovascular complication in patients with MFS is pro- gressive dilatation of the ascending aorta, initially involving the sinuses of Valsalva. 6 Although patients affected with CCA were initially felt not to have aortic involvement, three children under 6 years of age with CCA have had dilated aortic roots, further blurring the clinical distinction between the two syndromes. 5 The overlap in the clinical features has a molecular basis; CCA and MFS result from mutations in two homologous genes, FBN2 and FBN1, respectively. 5 7-9

The FBN2 Gene: New Mutations, Locus-Specific Database (Universal Mutation Database FBN2), and Genotype-Phenotype Correlations

Congenital contractural arachnodactyly (CCA) is an extremely rare disease, due to mutations in the FBN2 gene encoding fibrillin‐2. Another member of the fibrillin family, the FBN1 gene, is involved in a broad phenotypic continuum of connective‐tissue disorders including Marfan syndrome. Identifying not only what is in common but also what differentiates these two proteins should enable us to better comprehend their respective functions and better understand the multitude of diseases in which these two genes are involved. In 1995 we created a locus‐specific database (LSDB) for FBN1 mutations with the Universal Mutation Database (UMD) tool. To facilitate comparison of identified mutations in these two genes and search for specific functional areas, we created an LSDB for the FBN2 gene: the UMD‐FBN2 database. This database lists 26 published and six newly identified mutations that mainly comprise missense and splice‐site mutations. Although the number of described FBN2 mutations was low, the frequency of joint dislocation was significantly higher with missense mutations when compared to splice site mutations. The database is freely available at http://umd.be. Hum Mutat 0, 1–10, 2008.

Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin

A Mexican family with partial congenital nephrogenic diabetes insipidus (NDI) that resulted from a mutation in the aquaporin-2 water channel (AQP2) was characterized, and the source of this rare mutation was traced to the familys town of origin in Mexico. Affected individuals with profound polyuria and polydipsia were homozygous for an autosomal recessive missense V168M mutation in the AQP2 gene. Expression in oocytes revealed that, although retained in the endoplasmic reticulum (ER) to a great extent, a considerable amount of the partially functional AQP2-V168M was expressed at the plasma membrane, and that its ER retention was less than AQP2-T126M, a functional mutant in severe recessive NDI. None of the affected AQP2-V168M individuals had neurologic deficits, which also suggested a milder form of the disease. The homozygous individuals reported subjective improvement in polyuria and polydipsia with the use of dDAVP (1-desamino-8-D-arginine-vasopressin). When clinically tested, infusion of dDAVP at variable doses produced a partial increase in the urinary osmolality in homozygous individuals and decreased their water intake. Heterozygotes were unaffected when compared with controls. Samples were obtained from the population of the Mexican town of origin of the family; 30% of the population was heterozygous for the V168M AQP2 mutation and 1% was homozygous for the mutation. The high frequency of this rare mutation in the town provides evidence for an important health care problem in the village with consequences for future generations.

Towards computationally sound symbolic analysis of key exchange protocols

We present a cryptographically sound formal method for proving correctness of key exchange protocols. Our main tool is a fragment of a symbolic protocol logic. We demonstrate that proofs of key agreement and key secrecy in this logic imply simulatability in Shoups secure multi-party framework for key exchange. As part of the logic, we present cryptographically sound abstractions of CMA-secure digital signatures and a restricted form of Diffie-Hellman exponentiation, which is a technical result of independent interest. We illustrate our method by constructing a proof of security for a simple authenticated Diffie-Hellman protocol.

Automatic verification of parameterized data structures

Verifying correctness of programs operating on data structures has become an integral part of software verification. A method is a program that acts on an input data structure (modeled as a graph) and produces an output data structure. The parameterized correctness problem for such methods can be defined as follows: Given a method and a property of the input graphs, we wish to verify that for all input graphs, parameterized by their size, the output graphs also satisfy the property. We present an automated approach to verify that a given method preserves a given property for a large class of methods. Examples include reversals of linked lists, insertion, deletion and iterative modification of nodes in directed graphs. Our approach draws on machinery from automata theory and temporal logic. For a useful class of data structures and properties, our solution is polynomial in the size of the method and size of the property specification.

An FBN1 pseudoexon mutation in a patient with Marfan syndrome: confirmation of cryptic mutations leading to disease

AbstractMarfan syndrome (MFS) results from heterozygous mutations in FBN1. However, genetic analyses of deoxyribonucleic acid (DNA) from approximately 10–30% of MFS patients who meet diagnostic criteria do not reveal an identifiable FBN1 mutation. In a patient who met the diagnostic criteria for MFS, bidirectional DNA sequencing of exons and intron–exon boundaries of FBN1 failed to reveal a mutation. Assessment of the FBN1 message in dermal fibroblasts from the patient revealed insertion of a pseudoexon between exons 63 and 64. Sequencing of intron 63 identified a point mutation, IVS63+373, located near the middle of intron 63 of FBN1 that created a donor splice site in intron 63, leading to inclusion of a 93-bp fragment of intronic sequence in the FBN1 message. Identification of a novel pseudoexon mutation in FBN1, in association with a clinical diagnosis of MFS, confirms that cryptic mutations that are missed by the current DNA-based diagnostic methods have a causative role.

Paucity of skeletal manifestations in hispanic families with FBN1 mutations

Marfan syndrome (MFS) is an autosomal dominant condition with pleiotropic manifestations involving the skeletal, ocular, and cardiovascular systems. The diagnosis is based primarily on clinical involvement of these and other systems, referred to as the Ghent criteria. We have identified three Hispanic families from Mexico with cardiovascular and ocular manifestations due to novel FBN1 mutations but with paucity of skeletal features. The largest family, hMFS001, had a frameshift mutation in exon 24 (3075delC) identified as the cause of aortic disease in the family. Assessment of eight affected adults revealed no major skeletal manifestation of MFS. Family hMFS002 had a missense mutation (R1530C) in exon 37. Four members fulfilled the criteria for ocular and cardiovascular phenotype but lacked skeletal manifestations. Family hMFS003 had two consecutive missense FBN1 mutations (C515W and R516G) in exon 12. Eight members fulfilled the ocular criteria for MFS and two members had major cardiovascular manifestations, however none of them met criteria for skeletal system. These data suggest that individuals of Hispanic descent with FBN1 mutations may not manifest skeletal features of the MFS to the same extent as Caucasians. We recommend that echocardiogram, ocular examination and FBN1 molecular testing be considered for any patients with possible MFS even in the absence of skeletal features, including Hispanic patients.

Binary rewriting and call interception for efficient runtime protection against buffer overflows

Buffer overflow vulnerabilities are one of the most commonly and widely exploited security vulnerabilities in programs. Most existing solutions for avoiding buffer overflows are either inadequate, inefficient or incompatible with existing code. In this paper, we present a novel approach for transparent and efficient runtime protection against buffer overflows. The approach is implemented by two tools: Type Information Extractor and Depositor (TIED) and LibsafePlus. TIED is first used on a binary executable or shared library file to extract type information from the debugging information inserted in the file by the compiler and reinsert it in the file as a data structure available at runtime. LibsafePlus is a shared library that is preloaded when the program is run. LibsafePlus intercepts unsafe C library calls such as strcpy and uses the type information made available by TIED at runtime to determine whether it would be ‘safe’ to carry out the operation. With our simple design we are able to protect most applications with a performance overhead of less than 10%. Copyright

High throughput detection of small genomic insertions or deletions by Pyrosequencing

Small insertions or deletions of nucleotides are common polymorphic variations in the human genome and can result in a predisposition to disease. However, high throughput methods for detecting these variations are limited. This report describes a method to detect this variation based on sequencing the boundaries of nucleotide alterations using the Pyrosequencing technique. This method can optimally detect up to 100 base pair nucleotide insertions and deletions, and also complicated genomic rearrangements.