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C A Francomano

Publications and source records attributed to C A Francomano.

At least 55 records · Page 3Linked to original sources
PubMed1997

A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.

The underlying basis of many forms of syndromic craniosynostosis has been defined on a molecular level. However, many patients with familial or sporadic craniosynostosis do not have the classical findings of those craniosynostosis syndromes. Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p. In this instance, a new clinical syndrome is being defined on the basis of the molecular finding. In addition to the skull findings, some patients had abnormalities on radiographs of hands and feet, including thimble-like middle phalanges, coned epiphyses, and carpal and tarsal fusions. Brachydactyly was seen in some cases; none had clinically significant syndactyly or deviation of the great toe. Sensorineural hearing loss was present in some, and developmental delay was seen in a minority. While the radiological findings of hands and feet can be very helpful in diagnosing this syndrome, it is not in all cases clearly distinguishable on a clinical basis from other craniosynostosis syndromes. Therefore, this mutation should be tested for in patients with coronal synostosis.

Adult↗
PubMed1996

Brachydactyly type C gene maps to human chromsome 12q24.

Brachydactyly type C is an autosomal dominant disorder characterized by abnormal segmentation of the index and middle fingers segregating with a high degree of variable expression in members of the same family. We have followed up and studied members of the large kindred segregating with the brachydactyly type C phenotype described by Virgil Haws in 1963, and using genetic linkage analysis, we localized the susceptibility gene to human chromosome 12q24.

Chromosome Mapping↗
PubMed1996

Career development for women in academic medicine: Multiple interventions in a department of medicine.

OBJECTIVE: To determine the gender-based career obstacles for women in an academic department of medicine and to report the interventions to correct such obstacles (resulting from the evaluation) and the results of these interventions. DESIGN: Intervention study, before-after trial, with assessment of faculty concerns and perceived change through structured, self-administered questionnaires. SETTING: The Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Md. PARTICIPANTS: Full-time faculty. INTERVENTIONS: Multifaceted intervention from 1990 through 1995 to correct gender-based career obstacles reported by women faculty, including problem identification, leadership, and education of faculty, and interventions to improve faculty development, mentoring, and rewards and to reduce isolation and structural career impediments. MAIN OUTCOME MEASURES: Retention and promotion of deserving women faculty, salary equity, quality of mentoring, decreased isolation from information and colleagues, integration of women faculty into the scientific community, and decreased manifestations of gender bias. RESULTS: Junior women were retained and promoted, reversing previous experience, with a 550% increase in the number of women at the associate professor rank over 5 years (from 4 in 1990 to 26 in 1995). Interim 3-year follow-up showed a 183% increase in the proportion of women faculty who expected they would still be in academic medicine in 10 years (from 23% [7/30] in 1990 to 65% [30/46] in 1993). One half to two thirds of women faculty reported improvements in timeliness of promotions, manifestations of gender bias, access to information needed for faculty development, isolation, and salary equity. Men also reported improvements in these areas. CONCLUSIONS: The outcomes reported here indicate that it is possible to make substantive improvements in the development of women's careers, that an institutional strategy to this end can be successful in retaining women in academic medicine, and that such interventions are likely to benefit all faculty. Long-term interventions appear essential.

Academic Medical Centers↗
PubMed1996

The gene for the Ellis-van Creveld syndrome is located on chromosome 4p16.

Ellis-van Creveld syndrome (EVC) is an autosomal recessive disorder characterized by disproportionate dwarfism, polydactyly, and congenital heart disease. This rare disorder is found with increased frequency among the Old Order Amish community in Lancaster County, Pennsylvania. We have used linkage analysis to localize the gene responsible for the EVC phenotype in nine interrelated Amish pedigrees and three unrelated families from Mexico, Ecuador, and Brazil. We now report the linkage for the Ellis-van Creveld syndrome gene to markers on the distal short arm of human chromosome 4, with Zmax = 6.91 at theta = 0.02 for marker HOX7, in a region proximal to the FGFR3 gene responsible for the achondroplasia phenotype.

Brazil↗
PubMed1996

Exclusion of the MSX1 homeobox gene as the gene for the Ellis van Creveld syndrome in the Amish.

Ellis van Creveld syndrome (EVC) is an autosomal recessive disorder which has previously been mapped to human chromosome 4p16.1. This disorder is characterized by disproportionate dwarfism, polydactyly, cleft palate, natal teeth, and congenital heart disease. The MSX1 homeobox gene also maps to the 4p16.1 region. Msx gene transcripts in the mouse embryo are known to be involved in pattern formation of the developing limb bud and craniofacial bones. Thus, on the basis of both map location and known gene function, MSX1 was an excellent candidate as the causative gene for EVC. Nonetheless, direct DNA sequencing of both exons of the MSX1 gene in five affected individuals segregating with the EVC phenotype, as well as those of two obligate carriers, revealed no mutations in the coding region of the gene.

Amino Acid Sequence↗
PubMed1996

Bone dysplasias in man: molecular insights.

The recent explosion in the number of identified genes involved in the human skeletal dysplasias has dramatically advanced this particular field. While linkage efforts are mapping hereditary disorders of the skeleton at an ever accelerating pace, progress in the Human Genome Project is providing tools for rapid gene discovery after the map location is known. Emerging themes in the molecular analysis of the skeletal dysplasias include the identification of allelic series of disorders and the existence of mutational and genetic heterogeneity in many of these conditions. Allelic series include those conditions caused by mutations in the genes encoding type II collagen (COL2A1), cartilage oligomeric matrix protein (COMP), fibroblast growth factor receptor 3 (FGFR3) and the diastrophic dysplasia sulfate transporter (DTDST). The recognition of these phenomena has initiated the analysis of the relationship between disease phenotype and gene.

Anion Transport Proteins↗
PubMed1996

Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes.

Pfeiffer syndrome (PS; McKusick MIM 101,600) is an autosomal dominant craniosynostosis syndrome with characteristic craniofacial anomalies and broad thumbs and big toes. We have previously demonstrated genetic heterogeneity in PS and mapped a gene to chromosome 8 (ref. 3) and a second to chromosome 10 (ref. 4). The gene on chromosome 8 is the fibroblast growth factor receptor 1 (FGFR1) with a common mutation (C755G) predicting a Pro252Arg substitution. The gene on chromosome 10 is FGFR2 with several different mutations causing sporadic and familial PS (Table 1). We report a recurrent single point mutation in the FGFR3 gene, located on chromosome 4p, in ten unrelated families with craniosynostosis syndromes. This mutation (C749G) predicts a Pro250Arg amino acid substitution in the extracellular domain of the FGFR3 protein. Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively.

Acrocephalosyndactylia↗
PubMed1996

A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis.

Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in an arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.

Blotting, Southern↗
PubMed1995

Localization of the gene (SYM1) for proximal symphalangism to human chromosome 17q21-q22.

Proximal symphalangism, or Cushing symphalangism (MIM 185800), is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joints. Conductive deafness and reduced flexibility of the ankles have also been observed in affected individuals. We have used polymorphic markers throughout the genome to perform genetic linkage analysis in subsequent generations of the family originally described by Harvey Cushing. We have established linkage for this disorder to markers on chromosome 17 (17q21-q22), with Zmax = 6.98 at theta = 0.05 with marker D17S790.

Abnormalities, Multiple↗
PubMed1995

Association study of transforming growth factor alpha (TGF alpha) TaqI polymorphism and oral clefts: indication of gene-environment interaction in a population-based sample of infants with birth defects.

In this study of infants with isolated birth defects, 69 cleft palate only cases, 114 cleft lip with or without cleft palate cases, and 284 controls with noncleft birth defects (all born in Maryland between 1984 and 1992) were examined to test for associations among maternal exposures, genetic markers, and oral clefts. A significantly higher frequency of positive family history of birth defects among both groups of oral cleft cases compared with controls was seen in these data. While there was a modest increase in the less common C2 allele at the TaqI site in the transforming growth factor alpha (TGF alpha) locus among cleft palate only infants compared with the birth defect controls, the association appeared to reflect an underlying interaction between maternal smoking and infant genotype. This apparent gene-environment interaction was also found among those reporting no family history of any birth defect. Infants carrying the rarer C2 allele who were exposed to maternal smoking of 10 or fewer cigarettes per day showed a 6.16-fold increase in risk for cleft palate only (95% confidence interval 1.09-34.7), while similar infants whose mothers smoked more than 10 cigarettes per day showed an 8.69-fold higher risk (95% confidence interval 1.57-47.8). However, the dose-response relation was not significant.

Adult↗
PubMed1995

COL5A1: fine genetic mapping and exclusion as candidate gene in families with nail-patella syndrome, tuberous sclerosis 1, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos Syndrome type II.

COL5A1, the gene for the alpha 1 chain of type V collagen, has been considered a candidate gene for certain diseases based on chromosomal location and/or disease phenotype. We have employed 3'-untranslated region RFLPs to exclude COL5A1 as a candidate gene in families with tuberous sclerosis 1, Ehlers-Danlos syndrome type II, and nail-patella syndrome. In addition, we describe a polymorphic simple sequence repeat (SSR) within a COL5A1 intron. This SSR is used to exclude COL5A1 as a candidate gene in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and to add COL5A1 to the existing map of "index" markers of chromosome 9 by evaluation of the COL5A1 locus on the CEPH 40-family reference pedigree set. This genetic mapping places COL5A1 between markers D9S66 and D9S67.

Base Sequence↗
PubMed1995

Concentration of mutations causing Schmid metaphyseal chondrodysplasia in the C-terminal noncollagenous domain of type X collagen.

Schmid metaphyseal chondrodysplasia (SMCD) has previously been shown to be the result of mutations in the type X collagen gene, COL10A1. A further three mutations have been identified, including two nonsense mutations (Y268X, W651X) and a frameshift mutation (1856delCC). Each of the 10 SMCD mutations identified to date is within the C-terminal noncollagenous domain of type X collagen and three of five deletions initiated around the same nucleotide. This domain is believed to be involved in the initiation of collagen trimerization. The concentration of mutations within this domain is consistent with the hypothesis that the phenotype is the result of a reduction in the level of mature type X collagen due to the mutant polypeptide's inability to participate in trimer formation, although a dominant-negative mechanism cannot be discounted, on the basis of current evidence.

Amino Acid Sequence↗
PubMed1995

The gene for pycnodysostosis maps to human chromosome 1cen-q21.

Pycnodysostosis (OMIM 265800) is an autosomal recessive skeletal disorder first described by Maroteaux and Lamy that is characterized by short stature, increased bone density, delayed closure of cranial sutures, loss of the mandibular angle, dysplastic clavicles, dissolution of the terminal phalanges of the hands and feet, dental abnormalities and increased bone fragility. Patients have a typical appearance secondary to prominence of the calvarium, smallness of the facial features, prominent nose and micrognathia. The French painter, Henri de Toulouse Lautrec (1864-1901), is believed to have had the disorder. Although more than 100 cases have been reported, we are aware of only two large consanguinous pedigrees in which the pycnodysostosis disorder segregates. We have studied the segregation of the pycnodysostosis phenotype in a large consanguinous Mexican pedigree, the clinical features of which are very similar to those described in the Arab pedigree studied by Edelson et al. Here, we report linkage for the pycnodysostosis phenotype in the 1cen-q21 region of human chromosome 1, and discuss candidate genes for this skeletal disorder.

Base Sequence↗