Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present a patient with pansynostosis, hydrocephalus, seizures, extreme proptosis with luxation of the eyes out of the lids, apnea and airway obstruction, intestinal non-rotation, and severe developmental delay. His skeletal abnormalities include bilateral elbow ankylosis, radial head dislocation, and unilateral broad and deviated first toe. The phenotype of this patient is consistent with that previously reported in Pfeiffer syndrome type III, but is unusual for the lack of broad thumbs. Our patient most closely resembles the case described by Kerr et al. [1996: Am J Med Genet 66:138-143] as Pfeiffer syndrome type III with normal thumbs. Mutations in the genes for fibroblast growth factor receptors (FGFR) 1 and 2 have previously been seen in patients with Pfeiffer syndrome type I. The mutation identified in our patient, Ser351Cys in FGFR2, represents the first reported cause of Pfeiffer syndrome type III. An identical mutation was described once previously by Pulleyn et al., in a patient whose brief clinical description included cloverleaf skull, significant developmental delay, and normal hands and feet [Eur. J. Hum. Genet. 4: 283-291, 1996]. In our patient, previously performed single-strand conformation polymorphism analysis failed to detect a band shift; the mutation was identified only after independent sequence analysis.
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PMID:Phenotype of the fibroblast growth factor receptor 2 Ser351Cys mutation: Pfeiffer syndrome type III. 971 39

We report a boy with truncus arteriosus, dysmorphic features, developmental delay, passing hypotonia, short segment Hirschsprung disease (HSCR), and paroxysmal hypoventilation. FISH analysis showed an interstitial deletion in chromosome band 22q11.2 coinciding with the deletions found in DiGeorge syndrome and velocardiofacial syndrome. Mutation scanning of RET, GDNF, EDNRB, and EDN3, genes associated with Hirschsprung disease, showed no aberrations. Since we know of two more patients with velocardiofacial syndrome and HSCR, we hypothesise that a gene responsible for proper development of the enteric nervous system may be included in the 22q11.2 region.
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PMID:A Hirschsprung disease locus at 22q11? 1020 49

Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.
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PMID:The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. 1069 68

We report a de novo, apparently balanced (2;8)(q35;q21.2) translocation in a boy with developmental delay and autism. Cross species (colour) paint (Rx) and SKY FISH, forward and reverse chromosome painting, and FISH with subtelomeric probes were used to examine the patient's karyotype, but further rearrangements were not detected. FISH with region specific clones mapping near 2q35 and 8q21.2 breakpoints and STS mapping performed on the isolated derivative chromosomes were used to refine the location of the breakpoints further. A cryptic deletion of between 4.23 and 4.41 Mb in extent and involving at least 13 complete genes or transcription units was found at the breakpoint on 2q35. The deletion includes the promoter and 5' untranslated region of the paired box 3 (PAX3) gene. The child has very mild dystopia canthorum which may be associated with the PAX3 haploinsufficiency. The 8q21.2 breakpoint is within MMP16 which encodes matrix metalloproteinase 16. We postulate that the cryptic deletion and rearrangement are responsible for the patient's phenotype and that a gene (or genes) responsible for autism lies at 2q35 or 8q21.2. The results present a step towards identifying genes predisposing to autism.
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PMID:A cryptic deletion of 2q35 including part of the PAX3 gene detected by breakpoint mapping in a child with autism and a de novo 2;8 translocation. 1207 Feb 44

Saethre-Chotzen syndrome is a common craniosynostosis syndrome characterized by craniofacial and limb anomalies. Intragenic mutations of the TWIST gene within 7p21 have been identified as a cause of this disorder. There is phenotypic overlap with other craniosynostosis syndromes, and intragenic mutations in FGFR2 (fibroblast growth factor receptor 2) and FGFR3 (fibroblast growth factor receptor 3) have been demonstrated in the other conditions. Furthermore, complete gene deletions of TWIST have also been found in a significant proportion of patients with Saethre-Chotzen syndrome. We investigated 11 patients clinically identified as having the Saethre-Chotzen phenotype and 4 patients with craniosynostosis but without a clear diagnosis. Of the patients with the Saethre-Chotzen phenotype, four were found to carry the FGFR3 P250R mutation, three were found to be heterozygous for three different novel mutations in the coding region of TWIST, and two were found to have a deletion of one copy of the entire TWIST gene. Developmental delay was a distinguishing feature of the patients with deletions, compared to patients with intragenic mutations of TWIST, in agreement with the results of Johnson et al. [1998: Am J Hum Genet 63:1282-1293]. No mutations were found for the four patients with craniosynostosis without a clear diagnosis. Therefore, 9 of our 11 patients (82%) with the Saethre-Chotzen phenotype had detectable genetic changes in FGFR3 or TWIST. We propose that initial screening for the FGFR3 P250R mutation, followed by sequencing of TWIST and then fluorescence in situ hybridization (FISH) for deletion detection of TWIST, is sufficient to detect mutations in > 80% of patients with the Saethre-Chotzen phenotype.
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PMID:Genetic analysis of patients with the Saethre-Chotzen phenotype. 1291 May 3

We observed a novel 3.5 Mb 5q subtelomeric deletion in a 3-year-old girl with developmental delay, hypotonia and multiple minor anomalies. Comparison of her phenotype with the few published patients with terminal 5q35 deletions revealed several overlapping features, but also showed remarkable differences such as shortness of stature versus macrosomia. After the report of 5q35.3 microdeletions in Sotos syndrome we integrated the published BACs into the public draft sequence and exactly mapped the deletion size in our patient by FISH analysis with 15 BAC probes. We demonstrated that the deletion in our patient is immediately adjacent to the reported Sotos syndrome deletion site. Subtracting the symptoms of Sotos syndrome from the published patients with larger 5q35.3 deletions allowed us to delineate a distinct phenotype of prenatal lymphedema with increased nuchal translucency, pronounced muscular hypotonia and delay of reaching motor milestones, but speech development within normal limits, wide fontanels, failure to thrive with postnatal short stature, and multiple minor anomalies such as mildly bell-shaped chest, minor congenital heart disease, and a distinct facial gestalt, associated with the novel 3.5 Mb cryptic deletion. We further showed in our patient that the deletion of the LCT(4) synthase gene results in a reduction of cysteinyl leukotriene synthesis to about 65% compared to normal values. The prenatal nuchal lymphedema associated with this deletion syndrome my be related to the deletion of the FLT4 gene causing autosomal dominant primary lymphedema and contributes to the differential diagnosis of increased fetal nuchal translucency.
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PMID:A novel 5q35.3 subtelomeric deletion syndrome. 1290 Aug 93

We report molecular cytogenetic characterization of ring chromosome 15 in three unrelated male patients with the karyotype 46,XY,r(15). One was a stillborn child with several malformations, and the other two cases showed pre- and postnatal growth retardation and developmental delay, common features for ring chromosome 15 syndrome. One of these patients also displayed clinical features resembling Prader-Willi syndrome (PWS). To delineate the extent of the deletion on chromosome 15, we have carried out fluorescence in situ hybridization (FISH) using bacterial artificial chromosomes (BACs) mapping to the distal long arm of chromosome 15. The deletion breakpoints clustered within a 4.5-6.5 Mb region proximal to the 15q telomere. Two deletions involved the same known genes, while the largest deletion observed in the stillborn child involved three additional genes, including the COUP-TFII gene, which has been suggested to play a role in heart development. The heart malformations, which are observed in this patient, are thus likely to be due to hemizygosity/haploinsufficiency of the COUP-TFII gene. In all three patients, the insulin-like growth factor I receptor gene (IGF1R) gene was deleted supporting the association between IGF1R and growth retardation seen in ring chromosome 15 syndrome.
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PMID:Molecular cytogenetic characterization of ring chromosome 15 in three unrelated patients. 1538 84

To date, most ring formations of chromosome 4 lose distal 4p and usually include the Wolf-Hirschhorn syndrome region [WHS]. We describe a case with r(4) in a girl who presented without features of WHS; she had mild developmental delay, deafness, short stature, obesity, and the onset of type 2 diabetes in adolescence, a distinctive phenotype. Although 4p was significantly deleted on Giemsa banding, the 4p junction was distal to the WHS and FGFR3 but proximal to the D4S3360 marker. The 4q breakpoint was close to the telomere. The phenotype appears different from previous patients with 4p- or r(4), which have had more extensive 4p deletion.
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PMID:Ring chromosome 4 in a patient with early onset type 2 diabetes, deafness, and developmental delay. 1608 3

We describe two patients who have hypochondroplasia with medial temporal lobe dysgenesis. This association has only been reported once before. Both patients had an FGFR3 mutation: 1620C --> A, resulting in Asn540Lys. FGFR3 is expressed in the brain during development and plays a role in hippocampal formation. We suggest FGFR3 mutations might cause cerebral malformations in hypochondroplasia as well as in thanatophoric dysplasia. Further neuroimaging studies of patients with hypochondroplasia and epilepsy or developmental delay may clarify the proportion of patients with hypochondroplasia who have this pattern of central nervous system abnormalities.
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PMID:Medial temporal lobe dysgenesis in hypochondroplasia. 1622 82

FGFR3 germline mutations cause autosomal dominant skeletal disorders including achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and Crouzon syndrome. Somatic mutations of FGFR3 have been identified in bladder cancer, multiple myeloma, and other neoplasms. FGFR3 mutations have also been detected in 40% of seborrheic keratoses (SKs) of the hyperkeratotic and acanthotic subtype, which are very common benign skin tumors. Using a multiplex SNaPshot assay that covers 11 activating FGFR3 mutations, we investigated a series of 27 SKs of the adenoid subtype. Mutations were detected in 23 of 27 (85%) adenoid SKs. R248C mutations were the most frequent mutation type. In two SKs, the A393E mutation was found, which has not been described in acanthotic and hyperkeratotic SKs so far. Three adenoid SKs displayed two simultaneous FGFR3 mutations. Adenoid SKs seem to be characterized by a higher frequency of FGFR3 mutations than hyperkeratotic and acanthotic SKs. The mechanism for the high rate of somatic FGFR3 mutations in these benign skin tumors remains elusive, but UV light exposure may play a potential role, especially in the R248C mutations.
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PMID:High frequency of FGFR3 mutations in adenoid seborrheic keratoses. 1677 99


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