A novel HRAS substitution (c.266C>G; p.S89C) resulting in decreased downstream signaling suggests a new dimension of RAS pathway dysregulation in human development

Abstract

Costello syndrome is caused by HRAS germline mutations affecting Gly12 or Gly13 in >90% of cases and these are associated with a relatively homogeneous phenotype. Rarer mutations in other HRAS codons were reported in patients with an attenuated or mild phenotype. Disease-associated HRAS missense mutations result in constitutive HRAS activation and increased RAFMEK-ERK and PI3K-AKT signal flow. Here we report on a novel heterozygous HRAS germline alteration, c.266C>G (p.S89C), in a girl presenting with severe fetal hydrops and pleural effusion, followed by a more benign postnatal course. A sibling with the same mutation and fetal polyhydramnios showed a Dandy– Walker malformation; his postnatal course was complicated by severe feeding difficulties. Their apparently asymptomatic father is heterozygous for the c.266C>G change. By functional analyses we identified reduced levels of active HRASS89C and diminished MEK, ERK and AKT phosphorylation in cells over-expressing HRASS89C, which represent novel consequences of disease-associated HRAS mutations. Given our patients’ difficult neonatal course and presence of this change in their asymptomatic father, we hypothesize that its harmful consequences may be time limited, with the late fetal stage being most sensitive. Alternatively, the phenotype may develop only in the presence of an additional as-yet-unknown genetic modifier. While the pathogenicity of the HRAS c.266C>G change remains unproven, our data may illustrate wide functional and phenotypic variability of germline HRAS mutations.

An attenuated phenotype of Costello syndrome in three unrelated individuals with a HRAS c.179G>A (p.Gly60Asp) mutation correlates with uncommon functional consequences

“…From this novel viewpoint, HRAS Gly60Asp may be unable to transmit incoming signals due to the formation of non-productive signaling complexes. Similarly, a germline HRAS alteration (c.266C>G; p.Ser89Cys) resulting in decreased HRAS downstream signaling was reported in siblings with clinical features reminiscent of Costello syndrome [Gripp et al, 2012b]. Furthermore, based on experiments with primary fibroblasts of patients with Costello syndrome, altered cellular response to growth factors rather than constitutive activation of HRAS downstream signaling molecules may contribute to the phenotype [Rosenberger et al, 2009].…”

Costello syndrome: Clinical phenotype, genotype, and management guidelines

“…Prenatally, renal anomalies are present in up to 83% of fetuses with CS and include echogenic kidneys as well as dilated renal pelvis and pyelectasis (Lorenz et al, ; Myers et al, ). Documented postnatal renal anomalies include echogenic kidneys, ectopic kidney(s), enlarged kidneys, dilated renal pelvis/pyelectasis/hydronephrosis, and renal collecting system anomalies (Dickson et al, ; Digilio et al, ; Gripp et al, ; Lin et al, ; Lo et al, ; Lorenz et al, ). Kidney stones may occur in children and adults (Assadi et al, ; Gripp, Stabley, et al, ; Sol‐Church et al, ) and a bladder stone has been documented (Assadi et al, ).…”

Attenuated phenotype of Costello syndrome and early death in a patient with an HRAS mutation (c.179G>T; p.Gly60Val) affecting signalling dynamics

“…These notions were adopted for HRAS germline mutations causing CS. However, several studies revealed a differentiated spectrum of mutational effects . Notably, the CS‐associated HRAS p.Gly60Asp mutation did not increase mitogen‐activated protein kinase (MAPK) and PI3K‐Akt signalling under basal growth conditions and upon EGF stimulation …”