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Germline KRAS, BRAF, and MAPK Mutations in Noonan and Cardio-Facio-Cutaneous-Syndrome« Back to Volume 22, Issue 3, September 2006 - Table of Contents The mitogen-activated protein kinase (MAPK) intracellular signal transduction system is one of several signaling systems employed by growth hormone, prolactin, epidermal growth factor, and other mitogens (Figure). The MAPK pathway is important for cell proliferation, growth, aging, and apoptosis. After a growth factor binds to its specific receptor, GRB2 (growth factor receptor-bound protein 2; chromosome 17q23-q25, OMIM 108355), a cytosolic adaptor protein with SH2 and SH3 domains, complexes with the cytoplasmic domain of the activated growth factor receptor. Subsequently, GRB2 interacts with PTPN11 (protein-tyrosine phosphatase, non-receptor type 11; chromosome 12q24.1, OMIM 176876) through SH2-SH3 bonding and then binds to the guanine nucleotide exchange factor-SOS1 (son of sevenless drosophila, homolog 1; chromosome 2p22-p21,OMIM 182530) to mediate growth factor-induced activation of RAS (rat sarcoma viral oncogene homolog; chromosome 11p15.5, OMIM 190020). The RAS family of GTP-binding proteins includes KRAS, NRAS, and HRAS, all composed of 189 non-identical amino acids. After activation by addition of GTP, RAS initiates signal transduction through a series of 3 tyrosine-serine/threonine kinases (phosphorylases) that culminates in phosphorylation and activation of several transcription factors such as activating protein-1 (AP-1), and signal transducer and activator of transcription (STAT) 5. Intrinsic RAS GTPase assisted by GTPase activating proteins degrades RAS-linked GTP to GDP, thus decreasing RAS signaling and depressing the activity of the MAPK pathway. The intermediary kinases in the MAPK pathway include in sequential order:
Ras/Raf/MEK/ERK signal transduction pathway and associated genetic syndromes. MAPK3 in turn phosphorylates AP-1, STAT-5, and other transcription factors. With somatic single point mutations at codons 12,13 or 61, RAS intrinsic GTPase activity is diminished and the RAS proteins retain GTP, permitting them to become oncogenic by generating unbridled intracellular signaling that leads to unregulated cell proliferation and hematologic, lung, intestinal, pancreatic, thyroid, gonadal, and other neoplasms. Mutations in several of the genes involved in MAPK signaling have been identified and associated with clinical disorders. Noonan syndrome (OMIM 163950) is an autosomal dominant disorder characterized by a “Turner-like” face, short stature, webbing of the neck, and right-sided anomalies of the heart as well as deafness, motor delay, and a clotting disorder. In approximately 45% of patients with Noonan syndrome, germline heterozygous gain-of-function missense mutations in PTPN11 have been identified.1 PTPN11 (also designated SHP2) is an intracellular protein tyrosine phosphatase; adjacent to its catalytic domain are 2 tandem SRC homology 2 (SH2) domains that permit PTPN11 to bind to other proteins with SH2 and SH3 domains and to remove phosphate groups from specific phosphotyrosine residues. Among the substrates of PTPN11 is GRB2. Activating mutations in the SH2 or protein tyrosine phosphatase domains of PTPN11 increase signal transduction through the MAPK pathway leading to the clinical manifestations of Noonan syndrome, although the cellular mechanism(s) by which they occur is (are) unknown at present.1 (Heterozygous gain-of-function mutations within the protein tyrosine phosphatase domain of PTPN11 have also been identified in the LEOPARD syndrome [OMIM 15100], an autosomal dominant disorder with café-au-lait spots and lentigines as well as features similar to those of Noonan syndrome.) The Costello or facio-cutaneo-skeletal syndrome (OMIM 218040) is characterized by short stature, excessive skin of the neck (webbing), fingers, palms, and soles, curly hair, perioral and perinasal papillomata, developmental delay, and increased susceptibility to neoplasia. In the majority of patients with Costello syndrome, heterozygous gain-of-function mutations in HRAS (V-HA-RAS-Harvey Rat Sarcoma Viral Oncogene Homolog; chromosome 11p15.5, OMIM 190020) (v.i.) have been found.2 The 3 articles presently reviewed document overlapping clinical manifestations and mutations in several genes within the MAPK signal transduction pathway. Schubbert et al report that the clinical manifestations of Noonan syndrome can also arise as a consequence of gain-of-function mutations in KRAS (V-KI-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog, chromosome 12p12.1, OMIM 190070), a gene “downstream” of PTP11. They identified de novo germline KRAS mutations in 5/174 subjects with Noonan syndrome without PTPN11 mutations. The most common mutation (present in 3 patients) was substitution of isoleucine for valine at amino acid 14 (Val14Iso); this mutation depressed intrinsic GTPase activity of KRAS. The cardio-facio-cutaneous syndrome (OMIM 115150) is associated with congenital heart disease (pulmonic stenosis, atrial septal defect, hypertrophic cardiomyopathy), distinctive face (high forehead, bitemporal narrowing, hypoplastic supraorbital ridge, depressed nasal bridge, angulated ears), cutaneous abnormalities (sparse hair, ichthyosis-like thickening), and developmental delay. Schubbert et al found a heterozygous mutation in KRAS in 1/12 patients with this syndrome. Niihori and colleagues also identified 2 de novo germline heterozygous mutations in KRAS in 3/43 patients with the cardio-facio-cutaneous syndrome. These investigators further demonstrated 8 heterozygous mutations in BRAF-encoding the serine/threonine kinase most immediately responsive to KRAS (Figure) in 16/40 patients with the cardio-facio-cutaneous syndrome; 6/8 mutations were localized to the catalytic domain of BRAF. The majority of the mutations in KRAS and BRAF increased signal transduction through the MAPK pathway. These investigators identified no mutations in PTPN11 in any patient with the cardio-facio-cutaneous syndrome nor did they find aberrations in KRAS or BRAF in any Noonan subjects. Rodriguez-Viciana and associates found 11 heterozygous gain-of-function BRAF mutations in 18/23 patients with the cardio-facio-cutaneous syndrome. They also identified 2 heterozygous, activating mutations in MAP2K1 and one such mutation in MAP2K2 in 3/5 patients with this disorder. First Editor’s CommentThe signal transduction pathway and associated genetic syndromes are shown in the figure. Mutations have now been found in several of the protein components of the MAPK signal transduction pathway. That Schubbert et al found 169 patients with clinical manifestations of Noonan syndrome without PTPN11 or KRAS mutations demonstrates the substantial genetic heterogeneity of this disorder and leads one to anticipate the identification of gene mutations in other components of the MAPK signal transduction pathway, perhaps involving SOS, MAPK3, guanosine nucleotide exchange factors, and/or GTPase activating proteins. Indeed, neurofibromin, the neurofibromatosis type 1-associated tumor suppressor product of NF1, is a GTPase activating protein for RAS. With the delineation of more and more specific gene mutations leading to clinically described disorders, it may well be time to redesignate such entities according to the gene mutation itself; eg, “Hyperactive RAS disease: type 1, 2 ...,” “Hyperactive PTPN11 disease: type 1,2 ...,” or according to the genetic pathway involved, eg, “The MAPK syndromes.” Indeed, all of the clinical disorders of this pathway share common features to a greater or lesser degree such as short stature, distinctive faces, developmental delay, congenital anomalies of the heart, and skin changes. With intimate knowledge of the basic abnormalities within the described syndromes, drugs might be devised that ameliorate the hyperactivity of the MAPK pathway and moderate its clinical manifestations. Prenatal diagnosis and perhaps even fetal gene therapy also loom as possible future therapeutic avenues. Allen W. Root, MD Second Editor’s CommentThe reader is referred to Vol. 22, No. 2 of GGH for a review of 3 papers dealing with the increased growth hormone resistance of PTPN11 accounting for the short stature of patients with Noonan syndrome.3 A similar resistance may also be present in other patients with syndromes with or without PTPN11 or KRAS mutations, as they all share common features and short stature. The availability of recombinant IGF-I and IGF-I/IGF BP3 may now allow treatment strategies not previously available. Fima Lifshitz, MD References - (linked to
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Volume 24 Number 1
May 2008
www.GGHjournal.com
ISSN 1932-9032
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