Abstract
Noonan syndrome is a genetic autosomal dominant disorder characterized by facial dysmorphy, short stature, delayed puberty and congenital heart defects. The first gene implicated in this syndrome is PTPN11, encoding protein tyrosine phosphatase SHP-2. Several studies worldwide have identified missense mutations in this gene in patients with Noonan syndrome. Our objective focused on mutations screening of PTPN11 on a Senegalese population with Noonan syndrome. Six patients clinically diagnosed with Noonan syndrome were included in this study. DNA was extracted from whole blood by phenol chloroform. Mutation screening was performed by bidirectional sequencing of amplified polymerase chain reaction (PCR) products of PTPN11 exons frequently mutated in Noonan syndrome. This study identified in two patients, a c.923A˃C mutation in exon 8, predicting Asn308Thr (N308T) on SHP-2 protein. This is the first time that this mutation is described in Noonan syndrome in Africa, while codon 308 was reported as a hot spot mutation site in other populations. Frequently reported amino acid substitutions were Asn308Asp and Asn308Ser. All these mutations affected the protein tyrosine phosphatase domain (PTP) of SHP-2 protein exerting a gain of function which would likely explain observed phenotypes in patients. Key words: Mutation, N308T, protein tyrosine phosphatise (PTP), SHP-2 protein, Noonan syndrome, Senegal.
Highlights
Noonan syndrome (NS, MIM 163950) is an autosomal dominant dismorphic syndrome described first by Noonan (1968)
The most frequently mutated exons reported in NS (3, 4, 7 and 8) and flanking introns of protein tyrosine phosphatase non receptor 11 (PTPN11) gene were amplified by polymerase chain reaction (PCR) with sets of primers as described previously (Tartaglia et al, 2002)
Amino-acid changes in interaction sites between protein tyrosine phosphatase domain (PTP) and N-Src homology 2 (SH2) domains or near these sites may lead to the switch of SHP-2 protein from its inactive form to an active form, which result in a dominant positive effect on the activation of the RAS/MAPK signaling pathway effect
Summary
Noonan syndrome (NS, MIM 163950) is an autosomal dominant dismorphic syndrome described first by Noonan (1968). Tartaglia et al (2001) reported that NS is caused by heterozygous missense mutations of the gene protein-tyrosinephosph- Several studies have reported mutation analysis of PTPN11 gene and genotype-phenotype correlation in NS in different geographical regions (Bertola et al, 2004; Pierpont et al, 2009; Sznajer et al, 2007; Tartaglia et al, 2006; Yoshida et al, 2004).
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