The First Noonan Syndrome Gene: PTPN11, Which Encodes the Protein Tyrosine Phosphatase SHP-2

RESEARCH NEWS

A review of: Tartaglia M, Mehler EL, Goldberg R et al. 2001 Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 29:465–468; and Tartaglia M, Kalidas K, Shaw A et al. 2002 PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 70:1555–1563

OONAN SYNDROME IS a common autoso- with hypertrophic cardiomyopathy. The JUDITH ALLANSON N mal dominant disorder character- prevalence of other heart defects, short ized by unusual facial features, short stat- cates there may be a significant shift of the stature, skeletal anomalies, cryptorchidism, ure, skeletal anomalies, and defects of the equilibrium favoring the active conforma- and developmental delay does not differ heart, the most common of which are pul- tion, implying a gain of function change. between the two groups. An understanding monary valve dysplasia and hypertrophic Functional data support the conclusions of of the increased prevalence of hypertrophic cardiomyopathy (1, 2). Intellectual handi- these energetic-based structural analyses. It cardiomyopathy in other genetic forms of cap, usually mild, and bleeding diatheses, seems likely that Noonan syndrome occurs Noonan syndrome awaits elucidation of are also found. Incidence is said to be 1 in due to excessive SHP-2 activity, which those disease genes. 1000-2500 births. In 1994, Noonan syn- may result in increased or decreased sig- The next step will be to evaluate drome was mapped to 12q24.1 and genetic naling through specific pathways. syndromes with features that overlap heterogeneity was documented (3). The Tartaglia and colleagues have gone on with those of Noonan syndrome, such search for a causative gene has recently to evaluate the PTPN11 gene in 119 unre- as cardio-facio-cutaneous syndrome borne fruit. lated individuals with Noonan syndrome, and LEOPARD syndrome, to define In 2001, Tartaglia and colleagues, rep- 49 from small families and 70 sporadic whether these conditions are distinct, resenting a multicenter consortium, used a cases. Mutations have been found in 45% allelic, or extreme phenotypes of this positional candidacy approach to demon- of this cohort. There is a significantly highly variable disorder. strate mutations in PTPN11 in two mod- higher prevalence of mutations in familial erate sized families and 11 unrelated indi- cases. The mutations are missense exonic viduals, 50% of those tested (4). PTPN11 1. Allanson JE 1987 Noonan syndrome. J Med Genet changes, several of them recurrent. The 24:9–13 was considered a candidate gene for vast majority continue to be located in or 2. Allanson JE 2001 Noonan syndrome. In: Cassidy Noonan syndrome because of its location, SB, Allanson JE (eds) Management of Genetic Syn- around the interacting surfaces of the N- dromes. Wiley, New York, pp 253–268 and because it’s protein product, SHP-2, is SH2 and PTP functional domains, but mu- 3. Jamieson CR, van der Burgt I, Brady AF, van Reen M, a key component of several signal trans- Elsawi MM, Hol F, Jeffery S, Patton MA, Mariman E tations in the C-SH2 domain and in the 1994 Mapping a gene for Noonan syndrome to the duction pathways that control protean de- peptide linking the N-SH2 and C-SH2 do- long arm of chromosome 12. Nat Genet 8: 357–360 velopmental processes, particularly cardiac 4. Tartaglia M, Mehler EL, Goldberg R, Zampino G, mains are now also described. No attempt Brunner HG, Kremer H, van der Burgt I, Crosby AH, semilunar valvulogenesis. has yet been made to look for large intra- Ion A, Jeffery S, Kalidas K, Patton MA, Kucherlapati PTPN11 is composed of two tandemly RS, Gelb BD 2001 Mutations in PTPN11, encoding genic deletions or duplications, changes in the protein tyrosine phosphatase SHP-2, cause Noonan arranged amino-terminal src-homology 2 the 3ÚTR, or promotor/enhancer regions. syndrome. Nat Genet 29:465–468 (SH-2) domains (N-SH2 and C-SH2), a 5. Tartaglia M, Kalidas K, Shaw A, Song X, Musat That PTPN11 mutations should cause DL, van der Burgt I, Brunner HG, Bertola DR, phosphotyrosine phosphatase (PTP) do- varied congenital anomalies, such as those Crosby A, Ion A, Kucherlapati RS, Jeffery S, Patton main and a carboxy-terminal tail (5). The MA, Gelb BD 2002 PTPN11 mutations in Noonan observed in Noonan syndrome, is consis- syndrome: molecular spectrum, genotype-phenotype missense mutations cluster in interacting tent with the well established role of this correlation, and phenotypic heterogeneity. Am J portions of the amino N-SH2 domain and protein in development—including meso- Hum Genet 70:1555–1563 the PTP domains, which are involved in dermal patterning, limb development, he- switching the protein between its inactive mopoietic cell differentiation, and signal- and active conformations. These amino ing mediated by epidermal growth factor Department of Genetics Children’s Hospital of Eastern Ontario acid substitutions are found in exons 3 and receptor during semilunar valvulogenesis. 401 Smyth Road 8, they have not been found in more than As might be expected, pulmonic stenosis is Ottawa, Ontario 200 controls, and they affect highly con- more prevalent among the subjects with K1H 8L1 served regions. An energetics-based struc- mutations than in the group without muta- Canada tural analysis of two N-SH2 mutants indi- tions. The opposite is true for individuals DOI: 10.1203/01.PDR.0000035197.12622.58

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