Effect on splicing of a silent FGFR2 mutation in Crouzon syndrome.
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Base Sequence↗
Biomedical subjects
E W Jabs
Publications and source records attributed to E W Jabs.
Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans.
Crouzon syndrome, an autosomal dominant condition characterized by craniosynostosis, ocular proptosis and midface hypoplasia, is associated with mutations in fibroblast growth factor receptor 2 (FGFR2) (refs 1-3). For example, we have identified 10 different mutations in the FGFR2 extracellular immunoglobulin III (IgIII) domain in 50% (16/32) of our Crouzon syndrome patients. All mutations described so far for other craniosynostotic syndromes with associated limb anomalies--Jackson-Weiss, Pfeiffer, and Apert--also occur in the extracellular domain of FGFR2, as well as FGFR1 for Pfeiffer syndrome. In contrast, only FGFR3 mutations have been reported in dwarfing conditions--achondroplasia, thanatophoric dysplasia, and hypochondroplasia. For achondroplasia, greater than 99% of mutations occur in the FGFR3 transmembrane domain. We now report the unexpected observation of a FGFR3 transmembrane domain mutation, Ala391Glu, in three unrelated families with Crouzon syndrome and acanthosis nigricans, a specific skin disorder of hyperkeratosis and hyperpigmentation. The association of non-dwarfing and even non-skeletal conditions with FGFR3 mutations reveals the potential for a wide range of FGFR pleiotropic effects as well as locus heterogeneity in Crouzon syndrome. Our study underscores the biologic complexity of the FGFR gene family.
Acanthosis Nigricans↗
Novel FGFR2 mutations in Crouzon and Jackson-Weiss syndromes show allelic heterogeneity and phenotypic variability.
Mutations have been reported for several craniosynostotic disorders in exon IIIa (exon U or 7) or IIIc (exon B or 9) of the fibroblast growth factor receptor 2 gene (FGFR2). Among the conditions with FGFR2 mutations are two autosomal dominant syndromes, Crouzon and Jackson-Weiss. In this study, 24 Crouzon and one Jackson-Weiss syndrome patients were screened for mutations in the two exons by direct sequencing, and mutations were detected in 28% (7/25) of all cases. Five different mutations were found including two novel (W290G, C342W) and two previously reported, recurrent mutations for Crouzon syndrome (A344A, S354C), and one new mutation for Jackson-Weiss syndrome (C342R). The W290G mutation was found in exon IIIa which is common to both alternatively spliced forms of FGFR2, BEK (expressed predominantly in primordial bones) and KGFR (expressed preferentially in epithelia). Atypical Crouzon syndrome features of epithelial-derived anal and/or external ear anomalies were present in the two affected family members with the mutation. This phenotype possibly reflects the expression of both mutant BEK and KGFR. In addition, the Jackson-Weiss syndrome mutation, C342R, in exon IIIc was observed previously in other craniosynostotic syndromes, Crouzon and Pfeiffer. These results underscore the allelic heterogeneity of these conditions and the complexity of the phenotypic consequences of FGFR2 mutations.
Alleles↗
Localization of the human stem cell tyrosine kinase-1 gene (FLT3) to 13q12-->q13.
We have previously reported the cloning of stem cell tyrosine kinase-1 (STK-1, gene symbol FLT3), the human homolog of the mouse Flk2/Flt3 gene (Small et al., 1994). This growth factor receptor is expressed in CD34+ human bone marrow (stem/progenitor) cells. We have mapped the gene for STK-1 using PCR screening of a human-rodent somatic cell hybrid panel, and fluorescence in situ molecular hybridization (FISH) of STK-1 genomic probes to mitotic chromosomes of normal human lymphocytes. The results of both analyses show that the gene for STK-1 (FLT3) localizes to chromosome 13q12-->q13.
Animals↗
Mutations in fibroblast growth factor receptors: phenotypic consequences during eukaryotic development.
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Animals↗
Analysis of phenotypic features and FGFR2 mutations in Apert syndrome.
A phenotypic and genotypic survey was conducted on 36 Apert syndrome patients. In all but one patient, an FGFR2 mutation, either S252W or P253R, was found in exon IIIa (exon U or 7). The frequency was 71% and 26%, for the mutations S252W and P253R, respectively. These mutations occur in the linker region between immunoglobulin-like domains II and III, which are involved in activation of the receptor by ligand binding and dimerization. The fact that one patient did not have a mutation in the same exon suggests further genetic heterogeneity in Apert syndrome. The frequencies of occurrence or means for measurements of 29 different clinical features (including severity of craniofacial features, syndactyly of the hands and feet, and multisystem involvement) were determined for all patients and for the two subgroups defined by their mutations. Comparison between the subgroups for the different clinical features was performed and suggested no statistically significant differences. These results are not unexpected, because the two common mutations for Apert syndrome alter FGFR2 at adjacent amino acids that are likely to have similar biological, and therefore phenotypic, consequences.
Acrocephalosyndactylia↗
Human and mouse chromosomal mapping of the myeloid cell leukemia-1 gene: MCL1 maps to human chromosome 1q21, a region that is frequently altered in preneoplastic and neoplastic disease.
The MCL1 gene, recently identified in a myeloid leukemia cell line, has sequence similarity to BCL2, the gene at the t(14;18) translocation in follicular lymphoma. The chromosomal location of MCL1 has now been determined. The human locus (MCL1) was mapped to the long arm of human chromosome 1q21, using the methods of in situ hybridization and somatic cell hybrid analysis. In the mouse, MCL1-related sequences were mapped to positions on two mouse chromosomes (chromosomes 3 and 5), using haplotype analysis of an interspecific cross. The location of the locus on mouse chromosome 3 (Mcl1) was homologous to that of MCL1 on human chromosome 1; the second locus (Mcl-rs on mouse chromosome 5) may represent a pseudogene. The proximal long arm of human chromosome 1, where MCL1 is located, is duplicated and/or rearranged in a variety of preneoplastic and neoplastic diseases, including hematologic diseases and solid tumors. MCL1 is thus a candidate gene for involvement in cancer.
Animals↗
Complete cDNA sequence of a human dioxin-inducible mRNA identifies a new gene subfamily of cytochrome P450 that maps to chromosome 2.
Previously, levels of a novel human mRNA, detected by a recombinant cDNA designated clone 1, were shown to be increased 50-fold in response to treatment of a keratinocyte cell line with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in part as a function of increased rates of gene transcription (Sutter, T.R., Guzman, K., Dold, K.M., and Greenlee, W.F. (1991) Science 254, 415-418). Here we report the complete corresponding 5.1-kilobase cDNA sequence. A single open reading frame that predicts a protein of 543 amino acid residues was determined by computer-assisted analysis of the cDNA sequence. This predicted protein identifies a new gene subfamily of cytochrome P450, cytochrome P4501B1 (CYP1B1), that maps to human chromosome 2. Southern blot analysis of genomic DNA indicates that the human CYP1B subfamily is likely to contain only this single gene. Northern blot analysis of RNA isolated from primary cultures of normal human epidermal keratinocytes showed approximately 100-fold increased levels of the CYP1B1 mRNA after treatment with 10 nM TCDD for 24 h. Low levels of constitutive CYP1B1 mRNA were detected in 15 different human tissue samples. These results indicate that CYP1B1 is expressed in many normal human tissues and advance our understanding of the complexity of a gene family of cytochromes P450 whose expression is altered by TCDD.
Amino Acid Sequence↗
A YAC contig of approximately 3 Mb from human chromosome 5q31-->q33.
The human chromosome 5q31--q33 region contains an interesting cluster of growth factor and receptor genes. In addition, several genetic disease loci have been localized within this region, but have not as yet been isolated as molecular clones. These include those loci involved in autosomal dominant limb-girdle muscular dystrophy, diastrophic dysplasia, Treacher Collins syndrome, and myeloid disorders associated with the 5q- syndrome. A yeast artificial chromosome (YAC) contig of this region would assist in the further localization and isolation of these genes. We have used YACs isolated from the Washington University and Centre d'Etude du Polymorphisme Humain YAC libraries, including YACs from the large insert (mega) YAC library to build a contig greater than 3 Mb in size. An STS content strategy coupled with limited walking from YAC ends was used to isolate 22 overlapping YACs with as much as sixfold coverage. A total of 20 STSs, derived from genes, anonymous sequences, and vector Alu-PCR or inverse PCR products, were used to compile this contig. The order of loci, centromere-GRL-D5S207-D5S70-D5S545-D5S546- D5S547-D5S68-D5S548-D5S210-D5S549- D5S686-ADRB2-D5S559-CSF1R-D5S551-RPS14+ ++-D5S519-SPARC-telomere, was derived from the overlapping clones. This contig and clones derived from it will be useful substrates in selecting candidate cDNAs for the disease loci in this interval.
Base Sequence↗
Localization of the human Mxi1 transcription factor gene (MXI1) to chromosome 10q24-q25.
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Base Sequence↗
Chromosomal localization of genes required for the terminal steps of oxidative metabolism: alpha and gamma subunits of ATP synthase and the phosphate carrier.
The terminal steps of oxidative phosphorylation include transport of phosphate and ADP into the mitochondrial matrix, synthesis of ATP in the matrix, and transport of the product ATP into the cytosol where it can be utilized to perform cellular work. Three nuclear genome encoded membrane proteins, namely, the phosphate carrier (PHC), the adenine nucleotide carrier (ANT), and the ATP synthase complex, consisting of at least 13 individual subunits, catalyze these reactions. The locations of the alpha and gamma subunits of the mitochondrial ATP synthase complex and the mitochondrial phosphate carrier, PHC, on human chromosomes were determined using cloned rat liver cDNA as probes. Human homologues of the alpha subunit are on chromosomes 9 and 18, the gamma subunit are on chromosomes 10 and 14, and the PHC was localized to chromosome 12.
Animals↗
Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.
Jackson-Weiss syndrome is an autosomal dominant condition characterized by craniosynostosis, foot anomalies and great phenotypic variability. Recently mutations in fibroblast growth factor receptor 2 (FGFR2) have been found in patients with another craniosynostotic syndrome, Crouzon syndrome. FGFR2 is a member of the tyrosine kinase receptor superfamily, having a high affinity for peptides that signal the transduction pathways for mitogenesis, cellular differentiation and embryogenesis. We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. In addition, in four of 12 Crouzon syndrome cases, we identified two new mutations and found two previously described mutations in the same region.
Alleles↗
Partial structure and mapping of the human myelin P2 protein gene.
The myelin P2 protein, a 14,800-Da cytosolic protein found primarily in peripheral nerves, belongs to a family of fatty acid binding proteins. Although it is similar in amino acid sequence and tertiary structure to fatty acid binding proteins found in the liver, adipocytes, and intestine, its expression is limited to the nervous system. It is detected only in myelin-producing cells of the central and peripheral nervous systems, i.e., the oligodendrocytes and Schwann cells, respectively. As part of a program to understand the regulation of expression of this gene, to determine its function in myelin-producing cells, and to study its role in peripheral nerve disease, we have isolated and characterized overlapping human genomic clones encoding the P2 protein. We report here on the partial structure of this gene, and on its localization within the genome. By using a panel of human-hamster somatic cell hybrids and by in situ hybridization, we have mapped the human P2 gene to segment q21 on the long arm of chromosome 8. This result identifies the myelin P2 gene as a candidate gene for autosomal recessive Charcot-Marie-Tooth disease type 4A.
Amino Acid Sequence↗
Genetics of craniofacial disorders.
Due to the many recent and complementary advances in developmental biology and molecular genetics, we are learning much about the genetics of craniofacial disorders. In particular there is new information regarding craniosynostosis and orofacial clefting, which are among the more common birth defects. The pathogenesis of craniosynostosis, as well as the newest developments in the study of the common craniosynostotic syndromes, is discussed in this review. Genes and chromosomal regions implicated in orofacial clefting are reviewed. Lastly, insights are given into the pathogenesis of common craniofacial malformations as provided by animal models of human disease.
Congenital Abnormalities↗
Localization of a putative human brain sodium channel gene (SCN1A) to chromosome band 2q24.
We have identified four putative human sodium channel gene sequences, 55 bp each, using the polymerase chain reaction (PCR) on total human placental DNA with primers specific for the cDNA sequence of the rat brain sodium channel I alpha (Scn1a) gene. One of these sequences was extended bidirectionally by genomic inverse-PCR to obtain a 1.6-kb fragment. Sequencing of this 1,556-bp fragment showed a 282-bp complete exon, which has 95% and 94% homology at the nucleotide and amino acid levels, respectively, with the rat Scn1a gene. We putatively assign this sequence as belonging to the gene coding the alpha-subunit of a human brain type I sodium channel (SCN1A). PCR on human x rodent somatic cell hybrids with primers derived from SCN1A localized this gene to chromosome 2. Fluorescence in situ hybridization to human metaphase chromosomes sublocalized the gene to chromosome band 2q24.
Base Sequence↗
A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis.
Craniosynostosis, the premature fusion of calvarial sutures, is a common developmental anomaly that causes abnormal skull shape. The locus for one autosomal dominant form of craniosynostosis has been mapped to chromosome 5qter. The human MSX2 gene localizes to chromosome 5, and a polymorphic marker in the MSX2 intron segregates in a kindred with the disorder with no recombination. Moreover, a histidine substitutes for a highly conserved proline at position 7 of the MSX2 homeodomain exclusively in affected members. In the mouse, transcripts of the Msx2 gene are localized to calvarial sutures. These results provide compelling evidence that the mutation causes this craniosynostosis syndrome.
Acrocephalosyndactylia↗
Saethre-Chotzen syndrome with familial translocation at chromosome 7p22.
Chromosome analysis of a male infant and his mother with Saethre-Chotzen syndrome demonstrated an apparently balanced translocation, t(2;7)(p23;p22). This association lends support to localization of the gene for Saethre-Chotzen syndrome to the 7p2 region and supports further involvement of gene(s) in the 7p22 region.
Acrocephalosyndactylia↗
Family with 22-derived marker chromosome and late-onset dementia of the Alzheimer type: II. Further cytogenetic analysis of the marker and characterization of the high-level repeat sequences using fluorescence in situ hybridization.
We have further characterized an unusual 22p+ marker chromosome with a double nucleolus organizer region (dNOR) previously identified in a family with late-onset dementia of the Alzheimer type. G-banding and morphology of the marker's q arm were typically normal. However, the p+ arm had a terminal cytological satellite and a GT-positive region at the midpoint. Standard C-banding documented 2 C-positive regions: one was associated with the primary centromere; the other, which was at the midpoint of the p arm, was not associated with a constriction. With replication-banding, there was a darkly staining region in the middle of the p+ arm that resembled the pericentromeric region of a chromosome 21 or 22. Fluorescence in situ hybridization with pXlr 101, a probe recognizing the full repeating unit of rDNA, indicated that the marker had an unusually larger rDNA region; with pU 1.2, a probe recognizing the human rDNA promoter, the signal was a doublet. The marker had 2 signals with a beta-satellite probe, and a second signal in addition to that present at the primary centromere under low stringency with alpha-satellite probes and a classic satellite probe. Immunostaining of chromosome spreads after R-banding and ultraviolet (UV) denaturation showed that the major portion of the marker's p arm was highly methylated.
Aged↗