Article

Diversity, parental germline origin, and phenotypic spectrum of de novo HRAS missense changes in Costello syndrome.

Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
Human Mutation (Impact Factor: 5.05). 04/2007; 28(3):265-72. DOI: 10.1002/humu.20431
Source: PubMed

ABSTRACT Activating mutations in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) have recently been identified as the molecular cause underlying Costello syndrome (CS). To further investigate the phenotypic spectrum associated with germline HRAS mutations and characterize their molecular diversity, subjects with a diagnosis of CS (N = 9), Noonan syndrome (NS; N = 36), cardiofaciocutaneous syndrome (CFCS; N = 4), or with a phenotype suggestive of these conditions but without a definitive diagnosis (N = 12) were screened for the entire coding sequence of the gene. A de novo heterozygous HRAS change was detected in all the subjects diagnosed with CS, while no lesion was observed with any of the other phenotypes. While eight cases shared the recurrent c.34G>A change, a novel c.436G>A transition was observed in one individual. The latter affected residue, p.Ala146, which contributes to guanosine triphosphate (GTP)/guanosine diphosphate (GDP) binding, defining a novel class of activating HRAS lesions that perturb development. Clinical characterization indicated that p.Gly12Ser was associated with a homogeneous phenotype. By analyzing the genomic region flanking the HRAS mutations, we traced the parental origin of lesions in nine informative families and demonstrated that de novo mutations were inherited from the father in all cases. We noted an advanced age at conception in unaffected fathers transmitting the mutation.

0 Bookmarks
 · 
123 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GDP release from GTPases is usually extremely slow and is in general assisted by external factors, such as association with guanine exchange factors (GEFs) or membrane embedded G protein-coupled receptors (GPCRs), which accelerate the release of GDP by several orders of magnitude. Intrinsic factors can also play a significant role; a single amino acid substitution in one of the guanine nucleotide recognition motifs, G5, results in a drastically altered GDP release rate, indicating that the sequence composition of this motif plays an important role in spontaneous GDP release. In the present study we used the GTPase domain from E. coli FeoB (EcNFeoB) as a model and applied biochemical and structural approaches to evaluate the role of all the individual residues in the G5 loop. Our study confirms that several of the residues in the G5 motif have an important role in the intrinsic affinity and release of GDP. In particular, a T151A mutant (third residue of the G5 loop) leads to a reduced nucleotide affinity and provokes a drastically accelerated dissociation of GDP.
    Bioscience Reports 11/2014; DOI:10.1042/BSR20140152 · 2.85 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Craniofacial characteristics are highly informative for clinical geneticists when diagnosing genetic diseases. As a first step towards the high-throughput diagnosis of ultra-rare developmental diseases we introduce an automatic approach that implements recent developments in computer vision. This algorithm extracts phenotypic information from ordinary non-clinical photographs and, using machine learning, models human facial dysmorphisms in a multidimensional 'Clinical Face Phenotype Space'. The space locates patients in the context of known syndromes and thereby facilitates the generation of diagnostic hypotheses. Consequently, the approach will aid clinicians by greatly narrowing (by 27.6-fold) the search space of potential diagnoses for patients with suspected developmental disorders. Furthermore, this Clinical Face Phenotype Space allows the clustering of patients by phenotype even when no known syndrome diagnosis exists, thereby aiding disease identification. We demonstrate that this approach provides a novel method for inferring causative genetic variants from clinical sequencing data through functional genetic pathway comparisons.DOI: http://dx.doi.org/10.7554/eLife.02020.001.
    eLife Sciences 06/2014; 3:e02020. DOI:10.7554/eLife.02020 · 8.52 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Costello syndrome is a rare, autosomal dominant syndrome caused by activating missense mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS), most often p.G12S. Several rare mutations have consistently been associated with a more severe phenotype which is often lethal in infancy. Cause of death is most often respiratory failure with hypertrophic cardiomyopathy playing a significant role in morbidity. Impaired fibroblast elastogenesis is thought to contribute to the Costello phenotype, but reports of histologic evidence of disordered elastogenesis at autopsy are limited. We report a patient with Costello syndrome due to a rare tandem base substitution (c.35_36GC>AA) resulting in the p.G12E missense change. The proband died at age 3 months from respiratory failure, with minimal evidence for cardiomyopathy. Autopsy disclosed pulmonary vascular dysplasia affecting small arteries and veins associated with abnormal elastin distribution in tortuous dilated arteries and veins, with non-uniform wall thickness and semi-obstructive lesions at artery branch points typical of early pulmonary hypertensive vascular disease. Elastic fibers in the dermis were abnormally short and fragmented. This case suggests that disordered elastogenesis in the pulmonary vasculature and undiagnosed (or underdiagnosed) pulmonary hypertension may contribute to morbidity in patients with Costello syndrome. Key words: Costello syndrome, elastin, HRAS, pulmonary, pulmonary hypertension, vasculopathy.
    Pediatric and Developmental Pathology 08/2014; 17(6). DOI:10.2350/14-05-1488-OA.1 · 0.86 Impact Factor