Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients

ABSTRACT: BACKGROUND: Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrome characterized by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies, and immunological defects. Recently mutations in the histone methyl transferase MLL2 gene have been identified as its underlying cause. METHODS: Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intron-exon junctions. The putative causal and possible functional effect of each nucleotide variant identified was estimated by in silico prediction tools. RESULTS: We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. CONCLUSIONS: This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification of a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecular mechanisms underlying this disease, establish genotype-phenotype correlations and improve clinical management

What's in a Sign? Trademark Law and Economic Theory

Abstract: The aim of this paper is to summarise the extant theory as it relates to the economics of trademark, and to give some suggestions for further research with reference to distinct streams of literature. The proposed line of study inevitably looks at the complex relationship between signs and economics. Trademark is a sign introduced to remedy a market failure. It facilitates purchase decisions by indicating the provenance of the goods, so that consumers can identify specific quality attributes deriving from their own, or others', past experience. Trademark holders, on their part, have an incentive to invest in quality because they will be able to reap the benefits in terms of reputation. In other words, trademark law becomes an economic device which, opportunely designed, can produce incentives for maximising market efficiency. This role must, of course, be recognised, as a vast body of literature has done, with its many positive economic consequences. Nevertheless, trademark appears to have additional economic effects that should be properly recognized: it can determine the promotion of market power and the emergence of rent-seeking behaviours. It gives birth to an idiosyncratic economics of signs where very strong protection tends to be assured, even though the welfare effects are as yet poorly understood. In this domain much remains to be done and the challenge to researchers is open

Defining the phenotype associated with microduplication reciprocal to Sotos syndrome microdeletion.

NSD1 point mutations, submicroscopic deletions and intragenic deletions are the major cause of Sotos syndrome, characterized by pre-postnatal generalized overgrowth with advanced bone age, learning disability, seizures, distinctive facial phenotype. Reverse clinical phenotype due to 5q35 microduplication encompassing NSD1 gene has been reported so far in 27 cases presenting with delayed bone age, microcephaly, failure to thrive and seizures in some cases, further supporting a gene dosage effect of NSD1 on growth regulation and neurological functions. Here we depict the clinical presentation of three new cases with 5q35 microduplication outlining a novel syndrome characterized by microcephaly, short stature, developmental delay and in some cases delayed bone maturation, without any typical facial or osseous anomalies

Mutation spectrum of MLL2 in a cohort of Kabuki syndrome patients

Kabuki syndrome (Niikawa-Kuroki syndrome) is a rare, multiple congenital anomalies/mental retardation syndrom characterizes by a peculiar face, short stature, skeletal, visceral and dermatoglyphic abnormalities, cardiac anomalies and immunological defects. recently mutations in the histone methy transferase MLL2 gene have been identified as its underlying cause. Genomic DNAs were extracted from 62 index patients clinically diagnosed as affected by Kabuki syndrome. Sanger sequencing was performed to analyze the whole coding region of the MLL2 gene including intro-exon juctions. The putative causal and possible functional effect of each nucleotide variant identified estimated by in silico prediction tools. We identified 45 patients with MLL2 nucleotide variants. 38 out of the 42 variants were never described before. Consistently with previous reports, the majority are nonsense or frameshift mutations predicted to generate a truncated polypeptide. We also identified 3 indel, 7 missense and 3 splice site. This study emphasizes the relevance of mutational screening of the MLL2 gene among patients diagnosed with Kabuki syndrome. The identification od a large spectrum of MLL2 mutations possibly offers the opportunity to improve the actual knowledge on the clinical basis of this multiple congenital anomalies/mental retardation syndrome, design functional studies to understand the molecula mechanism underlying this disease, establish genotype-phenotype correlations and improve clinical management

The role of neurexins and neuroligins in autism

Autistic spectrum disorder (ASD) is a common, chronic psychiatric disorder for which the current generation of therapeutics are limited in their success at alleviating the neurobehaviors. While it is well established that both genetic and environmental factors contribute to the disorder, there is a lack of understanding about how ASD alters multiple domains of brain function. Identifying genes that are associated with ASD, and then relating how these genetic alterations affect brain structure and function is important to furthering our ability to design treatment and prevention strategies. Recent genome screening using copy number variant (CNV) analysis has identified deletions and duplications within the neurexin and neuroligin genes in patients with ASDs, highlighting their potential importance in ASD research. Neurexins and neuroligins are synaptic cell adhesion molecules and are found at the presynapse and postsynapse, respectively, of both excitatory and inhibitory cells. Neuroligins and leucine-rich repeat transmembranes bind to neurexins and convey a role in synaptic function and maintenance. However, little is known about how alterations within the genes encoding these proteins disrupt biological processes. Here we discuss the functional role of neurexins and neuroligins, the genetic evidence for their involvement in ASD and studies with transgenic mice to elucidate the consequences of these mutations