IHSSANE EL BOUCHIKHI, IMANE SAMRI, MOHAMMED IRAQUI HOUSSAINI, SAAID TRHANINT, LAILA BOUGUENOUCH, HANANE SAYEL, MOUSTAPHA HIDA, SAMIR ATMANI, KARIM OULDIM

The first PTPN11 mutations in hotspot exons reported in Moroccan children with Noonan syndrome and comparison of mutation rate to the previous studies

Background/aim: Noonan syndrome is an autosomal dominant disorder with an incidence of 1/1000?2500. It results from protein-tyrosine phosphatase, nonreceptor type 11 (PTPN11) mutations in roughly 50% of cases. Mutational screening of PTPN11 has been carried out in different populations. Thus, the aim of this study was to screen, for the first time, PTPN11 mutations in a series of Moroccan Noonan syndrome patients. Materials and methods: We used bidirectional sequencing of exons 3 and 8, considered as PTPN11 mutation hot spots, and then compared the rate of mutational events of these exons between different populations using chi-square and Fisher?s exact tests. Results: We detected 3 heterozygous mutations (Asp61Gly, Tyr63Cys, and Asn308Ser) in 4 individuals of 16 sporadic patients (25%). The rate of mutation in our cohort did not differ from that of other populations. However, we found significant differences in the mutation rate of exon 8 between one Japanese cohort and some populations, which requires more investigations to be explained. Conclusion: The present study allowed identification of mutations clustered in exons 3 and 8 of the PTPN11 gene in a Moroccan Noonan syndrome cohort and enabled us to give appropriate genetic counseling to the mutation-positive patients.

Anahtar Kelimeler:

Noonan syndrome, PTPN11, mutation analysis, SHP-2, mutation rate comparison

The first PTPN11 mutations in hotspot exons reported in Moroccan children with Noonan syndrome and comparison of mutation rate to the previous studies

Keywords:

Noonan syndrome, PTPN11, mutation analysis, SHP-2, mutation rate comparison,

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Noonan JA. Hypertelorism with Turner phenotype: a new syndrome with associated congenital heart disease. Am J Dis Child 1968; 116: 373–380. 2. Allanson JE. Noonan syndrome. J Med Genet 1987; 24: 9–13.
van der Burgt I, Thoonen G, Roosenboom N, Assman- Hulsmans C, Gabreels F, Otten B, Brunner HG. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr 1999; 135: 707–713.
Bastien L, Ramachandran C, Liu S, Adam M. Cloning, expression and mutational analysis of SH-PTP2, human protein-tyrosine phosphatase. Biochem Biophys Res Commun 1993; 196: 124–133.
Neel BG, Gu H, Pao L. The ‘Shp’ing news: SH2 domain- containing tyrosine phosphatases in cell signaling. Trends Biochem Sci 2003; 28: 284–293. 8. Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, Shoelson SE. Crystal structure of the tyrosine phosphatase SHP-2. Cell 1998; 92: 441–450.
Sarkozy A, Conti E, Seripa D, Digilio MC, Grifone N, Tandoi C, Fazio VM, Di Ciommo V, Marino VB, Pizzuti A et al. Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and Leopard syndromes. J Med Genet 2003; 40: 704–708.
Kosaki K, Suzuki T, Muroya K, Hasegawa T, Sato S, Matsuo N, Kosaki R, Nagai T, Hasegawa Y, Ogata T. PTPN11 protein tyrosine phosphatase, nonreceptor-type 11: mutations in seven Japanese patients with Noonan syndrome. J Clin Endocrinol Metab 2002; 87: 3529–3533.
Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW. Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. J Pediatr 2011; 159: 1029–1035.
Hung CS, Lin JL, Lee YJ, Lin SP, Chao MC, Lo FS. Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome. J Formos Med Assoc 2007; 106: 169–172.
Bertola DR, Pereira AC, Albano LMJ, De Oliveira PSL, Kim CA, Krieger JE. PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype. Genet Test 2006; 10: 186–191.
van der Burgt I, Berends E, Lommen E, van Beersum S, Hamel B, Mariman E. Clinical and molecular studies in a large Dutch family with Noonan syndrome. Am J Med Genet 1994; 53: 187–191.
Tartaglia M, Kalidas K, Shaw A, Song X, Musat DL, van der Burgt I, Brunner HG, Bertola DR, Crosby A, Ion A et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype–phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70: 1555–1563.
Jongmans M, Sistermans EA, Rikken A, Nillesen WM, Tamminga R, Patton M, Maier EM, Tartaglia M, Noordam K, van der Burgt I. Genotypic and phenotypic characterization of Noonan syndrome: new data and review of the literature. Am J Med Genet A 2005; 134A: 165–170.
O’Reilly AM, Pluskey S, Shoelson SE, Neel BG. Activated mutants of SHP-2 preferentially induce elongation of Xenopus animal caps. Mol Cell Biol 2000; 20: 299–311.
Niihori T, Aoki Y, Ohashi H, Kurosawa K, Kondoh T, Ishikiriyama S, Kawame H, Kamasaki H, Yamanaka T, Takada F et al. Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia. J Hum Genet 2005; 504: 192–202.
Zenker M, Buheitel G, Rauch R, Koenig R, Bosse K, Kress W, Tietze HU, Doerr HG, Hofbeck M, Singer H et al. Genotype– phenotype correlations in Noonan syndrome. J Pediatr 2004; 144: 368–374.
Yoshida R, Hasegawa T, Hasegawa Y, Nagai T, Kinoshita E, Tanaka Y, Kanegane H, Ohyama K, Onishi T, Hanew K et al. Protein-tyrosine phosphatase, nonreceptor type 11 mutation analysis and clinical assessment in 45 Patients with Noonan syndrome. J Clin Endocrinol Metab 2004; 89: 3359–3364.
Ferrero GB, Baldassarre G, Delmonaco AG, Biamino E, Banaudi E, Carta C, Rossi C, Silengo MC. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet 2008; 51: 566–572.
Ko JM, Kim JM, Kim GH, Yoo HW. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype–phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet 2008; 53: 999–1006.
Musante L, Kehl HG, Majewski F, Meinecke P, Schweiger S, Gillessen-Kaesbach G, Wieczorek D, Hinkel GK, Tinschert S, Hoeltzenbein M et al. Spectrum of mutations in PTPN11 and genotype–phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome. Eur J Hum Genet 2003; 11: 201–206.
Qu CK, Yu WM, Azzarelli B, Feng GS. Genetic evidence that Shp-2 tyrosine phosphatase is a signal enhancer of the epidermal growth factor receptor in mammals. P Natl Acad Sci USA 1999; 96: 8528–8533.
Chen B, Bronson RT, Klaman LD, Hampton TG, Wang JF, Green PJ, Magnuson T, Douglas PS, Morgan JP, Neel BG. Mice mutants for Egfr and Shp2 have defective cardiac semilunar valvulogenesis. Nat Genet 2000; 24: 296–299.
Feng GS. Shp-2 tyrosine phosphatase: signaling one cell or many. Exp Cell Res 1999; 253: 47–54.
Tamir I, Dal Porto JM, Cambier JC. Cytoplasmic protein tyrosine phosphatase SHP-1 and SHP-2: regulators of B cell signal transduction. Curr Opin Immunol 2000; 12: 307–315.
Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A, Dallapiccola B. Grouping of multiple- lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002; 71: 389–394.
Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics 2010; 126: 746–59.
Tartaglia M, Niemeyer CM, Fragale A, Song X, Buechner J, Jung A, Hählen K, Hasle H, Licht JD, Gelb BD. Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 2003;34: 148–150.
Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007; 39: 70–74.
Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007; 39: 1013–1017.
Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, Digilio C, Palleschi A, Pizzuti A, Grammatico P et al. Germline missense mutations affecting KRAS isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet 2006; 79: 129–135.