Developmental Syndromes

MEK/MAPK signaling is crucial at multiple stages of embryonic development.  For example, increased MAPK activity triggers meiotic maturation of oocytes and maintains cell cycle arrest at metaphase II in eggs prior to fertilization [124,125].  In addition, MAPK signaling is required for mesoderm induction during gastrulation [126].  At later stages of embryogenesis, the spatial and temporal control of active MAPK expression is exquisitely regulated in Drosophila, Xenopus, and mice [127,128,129].  In mice, sustained MAPK activity is detected in the ectoplacental cone, extraembryonic ectoderm, limb buds, branchial arches, and frontonasal process, as well as in the tail bud, forebrain, midbrain-hindbrain boundary, foregut, and liver primordia; transient MAPK activity is seen in the neural crest, peripheral nervous system, nascent blood vessels, and anlagen of the eye, ear, and heart [127].  Further, as might be expected, disruption of MEK/MAPK signaling has deadly consequences: gene targeting of KRAS or BRAF in mice results in death at mid-gestation [99,130], and MEK1-null mice die in utero with extensive defects in placental vascularization [103].

Given the multiple, key roles for MAPK signaling in embryonic development, it might reasonably have been predicted that germline mutations in this pathway would be embryonic lethal and so not be associated with specific developmental disorders.  However, nature has chosen to remind us how little we truly understand its complexities.  Rodriguez-Viciana et al. [131] and Niihori et al. [132] showed in recent issues of Science and Nature Genetics, respectively, that genetic mutations in KRAS, BRAF, MEK1, and MEK2 are associated with cardio-facio-cutaneous (CFC) syndrome.  CFC is a rare, autosomal and presumably dominant syndrome characterized by distinctive facial features, cardiac anomalies, hair and skin abnormalities, postnatal growth deficiency, and hypotonia [133].  Rodriguez-Viciana’s group screened a panel of blood samples from CFC patients for germline mutations in this pathway and found 11 different missense mutations in BRAF (9 of which had not been previously identified) in 18/23 patients.  Likewise, Niihori’s group screened for mutations in 43 samples and found germline KRAS and BRAF mutations in 3 and 19 patients, respectively.  No mutations were detected in the remaining 24 patient samples. Rodriguez-Viciana’s group also found that 3 of their remaining 5 patients harbored novel mutations in MEK1 and MEK2.  This is particularly noteworthy since it is the first identified instance of naturally occurring mutations in these genes.  Their observations also offer interesting insight into the biochemistry of MEK 1 and 2 because none of the mutated residues had previously been demonstrated to influence MEK biologic activities.

While most of the mutations that Rodriguez-Viciana et al. identified caused constitutive activation of the MEK pathway, at least one (G596V BRAF) appeared to be deficient in its ability to activate MEK.  This seems paradoxical, because it suggests that a similar phenotype may be caused by both activating and inactivating mutations in BRAF.  A similar situation exists for the related autosomal dominant Noonan (NS) and LEOPARD syndromes (LS), which are caused by gain-of-function mutations and inactivating mutations in the protein tyrosine phosphatase PTP11 (SHP2), leading to constitutive [134,135] or impaired MAPK activation [136], respectively.  If the developmental processes underlying these syndromes require a transient activation of MAPK, then the dampened or sustained elevation of MAPK activity may be sufficient to disrupt it.  Alternatively, loss of MAPK signaling may trigger activation of a compensatory mechanism, such as an alternative RAF signaling pathway that mimics sustained activation of this pathway and elicits a similar phenotypic result.

CFC, NS, and LS, as well as Costello Syndrome (CS; an autosomal dominant disease that has been linked to activating mutations in HRAS [137,138]), each cause a similar array of phenotypic consequences including facial dysmorphia, cardiomyopathy, and abnormal growth.  Each of these syndromes also carries with it an elevated risk of malignancy.  Patients with CS have increased incidence of rhabdomyosarcoma, transitional cell carcinoma, and neuroblastoma [139]; NS patients, of rhabdomyosarcoma, juvenile myelomonocytic leukemia, and acute lymphoblastic leukemia [140]; and LS patients, of acute myelogenous leukemia and neuroblastoma [141,142]. CFC has not been definitively linked with malignancies, though this may be a reflection of the limited number of patients with this disease.  In one respect, this is not surprising given that somatic mutations in KRAS and BRAF have been identified in many cancers and that activated MAPK or elevated MAPK expression has been detected in a variety of human tumors.  What is perplexing, though, is that each of these syndromes should be associated with such a narrow, yet distinct, range of malignancies.  The results of these latest studies indicate that tissue-specific mechanisms that repress elevated BRAF/MEK signaling must exist and that these must function at the level of MAPK signaling or at a later stage in the signaling cascade.