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C A Francomano

Publications and source records attributed to C A Francomano.

At least 37 records · Page 2Linked to original sources
PubMed1999

Characterization of the human talin (TLN) gene: genomic structure, chromosomal localization, and expression pattern.

Talin is a high-molecular-weight cytoskeletal protein, localized at cell-extracellular matrix associations known as focal contacts. In these regions, talin is thought to link integrin receptors to the actin cytoskeleton. Talin plays a key role in the assembly of actin filaments and in spreading and migration of various cell types. Talin proteins are found in a wide variety of organisms, from slime molds to humans. The human Talin (HGMW-approved symbol TLN) gene was previously mapped to chromosome 9p, but little was known of its sequence and genomic structure. To characterize human TLN further, we have isolated a single bacterial artificial chromosome clone, harboring the entire gene. The gene extends over more than 23 kb and consists of 57 exons. We have localized TLN to human chromosome band 9p13 by both fluorescence in situ hybridization and radiation hybrid mapping. Northern blot analysis detected TLN expression in various human tissues, including leukocytes, lung, placenta, liver, kidney, spleen, thymus, colon, skeletal muscle, and heart. Based on its chromosomal location, expression pattern, and protein function, we considered TLN as a candidate gene for cartilage-hair hypoplasia (CHH), an autosomal recessive metaphyseal chondrodysplasia, previously mapped to 9p13. We sequenced the entire TLN coding sequence in several CHH patients, but no functional mutations were detected.

Cartilage↗
PubMed1999

Identification of nine novel mutations in cartilage oligomeric matrix protein in patients with pseudoachondroplasia and multiple epiphyseal dysplasia.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are allelic disorders caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). PSACH is a dominant condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthritis. EDM1 is a less severe skeletal dysplasia associated with average to mild short stature, joint pain, and early-onset osteoarthritis. COMP is an extracellular matrix protein present in cartilage, ligament, and tendon tissues. Here, we report on nine novel mutations in COMP causing PSACH and EDM1. Four of these mutations are in exons 13C and 14 where no previous mutations had been reported. One of those mutations was identified in two separate EDM1 families. In addition, we have identified the first case of PSACH resulting from an expansion of the five aspartates in exon 17B. We are also reporting a mutation in a third PSACH family with somatic/germline mosaicism. Therefore, this report increases the range of mutations that cause PSACH and EDM1 and provides additional regions to target for mutational analysis.

Achondroplasia↗
PubMed1999

Small deletions in the type II collagen triple helix produce kniest dysplasia.

Kniest dysplasia is a moderately severe type II collagenopathy, characterized by short trunk and limbs, kyphoscoliosis, midface hypoplasia, severe myopia, and hearing loss. Mutations in the gene that encodes type II collagen (COL2A1), the predominant protein of cartilage, have been identified in a number of individuals with Kniest dysplasia. All but two of these previously described mutations cause in-frame deletions in type II collagen, either by small deletions in the gene or splice site alterations. Furthermore, all but one of these mutations is located between exons 12 and 24 in the COL2A1 gene. We used heteroduplex analysis to identify sequence anomalies in five individuals with Kniest dysplasia. Sequencing of the index patients' genomic DNA identified four new dominant mutations in COL2A1 that result in Kniest dysplasia: a 21-bp deletion in exon 16, an 18-bp deletion in exon 19, and 4-bp deletions in the splice donor sites of introns 14 and 20. A previously described 28-bp deletion at the COL2A1 exon 12-intron 12 junction, deleting the splice donor site, was identified in the fifth case. The latter three mutations are predicted to result in exon skipping in the mRNA encoded from the mutant allele. These data suggest that Kniest dysplasia results from shorter type II collagen monomers, and support the hypothesis that alteration of a specific COL2A1 domain, which may span from exons 12 to 24, leads to the Kniest dysplasia phenotype.

Base Sequence↗
PubMed1999

Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor receptor 3.

We previously discovered a novel missense mutation (Lys650Met) in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene in four unrelated individuals with a condition we called "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) [Tavormina et al., 1999: Am. J. Hum. Genet. 64:722-731]. Here we present a more detailed clinical account of the SADDAN phenotype. The FGFR3 Lys650Met mutation results in severe disturbances in endochondral bone growth that approach and overlap those observed in thanatophoric dysplasia, type I. However, this mutation is most often compatible with survival into adulthood. Other unusual bone deformities, such as femoral bowing with reverse (i.e., posterior apex) tibial and fibular bowing and "ram's horn" bowing of the clavicle, are also seen in some patients. In addition to skeletal dysplasia, progressive acanthosis nigricans, and central nervous system structural anomalies, seizures and severe developmental delays are observed in surviving SADDAN patients. Despite its location within the same FGFR3 codon as the thanatophoric dysplasia type II mutation (Lys650Glu) and a similar effect on constitutive activation of the FGFR3 tyrosine kinase, the Lys650Met is not associated with cloverleaf skull or craniosynostosis.

Acanthosis Nigricans↗
PubMed1999

Conservation of the Caenorhabditis elegans timing gene clk-1 from yeast to human: a gene required for ubiquinone biosynthesis with potential implications for aging.

Mutations in the Caenorhabditis elegans gene clk-1 have a major effect on slowing development and increasing life span. The Saccharomyces cerevisiae homolog COQ7 encodes a mitochondrial protein involved in ubiquinone biosynthesis and, hence, is required for respiration and gluconeogenesis. In this study, RT-PCR and 5' RACE were used to isolate both human and mouse clk-1/COQ7 homologs. Human CLK-1 was mapped to Chr 16(p12-13.1) by Radiation Hybrid (RH) and fluorescence in situ hybridization (FISH) methods. The number and location of human CLK1 introns were determined, and the location of introns II and IV are the same as in C. elegans. Northern blot analysis showed that three different isoforms of CLK-1 mRNA are present in several tissues and that the isoforms differ in the amount of expression. The functional equivalence of human CLK-1 to the yeast COQ7 homolog was tested by introducing either a single or multicopy plasmid containing human CLK-1 cDNA into yeast coq7 deletion strains and assaying for growth on a nonfermentable carbon source. The human CLK-1 gene was able to functionally complement yeast coq7 deletion mutants. The protein similarities and the conservation of function of the CLK-1/clk-1/COQ7 gene products suggest a potential link between the production of ubiquinone and aging.

Aging↗
PubMed1999

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Abnormalities, Multiple↗
PubMed1999

A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene.

We have identified a novel fibroblast growth factor receptor 3 (FGFR3) missense mutation in four unrelated individuals with skeletal dysplasia that approaches the severity observed in thanatophoric dysplasia type I (TD1). However, three of the four individuals developed extensive areas of acanthosis nigricans beginning in early childhood, suffer from severe neurological impairments, and have survived past infancy without prolonged life-support measures. The FGFR3 mutation (A1949T: Lys650Met) occurs at the nucleotide adjacent to the TD type II (TD2) mutation (A1948G: Lys650Glu) and results in a different amino acid substitution at a highly conserved codon in the kinase domain activation loop. Transient transfection studies with FGFR3 mutant constructs show that the Lys650Met mutation causes a dramatic increase in constitutive receptor kinase activity, approximately three times greater than that observed with the Lys650Glu mutation. We refer to the phenotype caused by the Lys650Met mutation as "severe achondroplasia with developmental delay and acanthosis nigricans" (SADDAN) because it differs significantly from the phenotypes of other known FGFR3 mutations.

Acanthosis Nigricans↗
PubMed1998

Sleep-disordered breathing in children with achondroplasia.

OBJECTIVE: Our objective was to characterize sleep-disordered breathing in 88 children with achondroplasia aged 1 month to 12.6 years. RESULTS: At the time of their initial polysomnography, five children had previously undergone tracheostomy, and seven children required supplemental oxygen. Initial polysomnography demonstrated a median obstructive apnea index of 0 (range, 0 to 19.2 apneas/hr). The median number of central apneas with desaturation per study was 0.5 (0 to 49), the median oxygen saturation nadir was 91% (50% to 99%), and the median peak end-tidal pCO2 was 47 mm Hg (36 to 87 mm Hg). Forty-two children (47.7%) had abnormal initial study results, usually caused by hypoxemia. Two children with severe obstructive sleep apnea eventually required continuous positive airway pressure therapy, and three additional children required tracheostomies. CONCLUSIONS: (1) Children with achondroplasia often have sleep-related respiratory disturbances, primarily hypoxemia. (2) The majority do not have significant obstructive or central apnea; however, a substantial minority are severely affected. (3) Tonsillectomy and adenoidectomy decreases the degree of upper airway obstruction in most but not all children with achondroplasia and obstructive sleep apnea. (4) Restrictive lung disease can present at a young age in children with achondroplasia.

Achondroplasia↗
PubMed1998

Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.

More than 97% of achondroplasia cases are caused by one of two mutations (G1138A and G1138C) in the fibroblast growth factor receptor 3 (FGFR3) gene, which results in a specific amino acid substitution, G380R. Sporadic cases of achondroplasia have been associated with advanced paternal age, suggesting that these mutations occur preferentially during spermatogenesis. We have determined the parental origin of the achondroplasia mutation in 40 sporadic cases. Three distinct 1-bp polymorphisms were identified in the FGFR3 gene, within close proximity to the achondroplasia mutation site. Ninety-nine families, each with a sporadic case of achondroplasia in a child, were analyzed in this study. In this population, the achondroplasia mutation occurred on the paternal chromosome in all 40 cases in which parental origin was unambiguous. This observation is consistent with the clinical observation of advanced paternal age resulting in new cases of achondroplasia and suggests that factors influencing DNA replication or repair during spermatogenesis, but not during oogenesis, may predispose to the occurrence of the G1138 FGFR3 mutations.

Achondroplasia↗
PubMed1998

Multiple molecular mechanisms underlying subdiagnostic variants of Marfan syndrome.

Mutations in the FBN1 gene, which encodes fibrillin-1, cause Marfan syndrome (MFS) and have been associated with a wide range of milder, overlap phenotypes. The factors that modulate phenotypic severity, both between and within families, remain to be determined. This study examines the relationship between the FBN1 genotype and phenotype in families with extremely mild phenotypes and in those that show striking clinical variation among apparently affected individuals. In one family, clinically similar but etiologically distinct disorders are segregating independently. In another, somatic mosaicism for a mutant FBN1 allele is associated with subdiagnostic manifestations, whereas germ-line transmission of the identical mutation causes severe and rapidly progressive disease. A third family cosegregates mild mitral valve prolapse syndrome with a mutation in FBN1 that can be functionally distinguished from those associated with the classic MFS phenotype. These data have immediate relevance for the diagnostic and prognostic counseling of patients and their family members.

Adult↗
PubMed1998

Mutation analysis of LMX1B gene in nail-patella syndrome patients.

Nail-patella syndrome (NPS), a pleiotropic disorder exhibiting autosomal dominant inheritance, has been studied for >100 years. Recent evidence shows that NPS is the result of mutations in the LIM-homeodomain gene LMX1B. To determine whether specific LMX1B mutations are associated with different aspects of the NPS phenotype, we screened a cohort of 41 NPS families for LMX1B mutations. A total of 25 mutations were identified in 37 families. The nature of the mutations supports the hypothesis that NPS is the result of haploinsufficiency for LMX1B. There was no evidence of correlation between aspects of the NPS phenotype and specific mutations.

Animals↗
PubMed1998

Genetic and physical mapping of the McKusick-Kaufman syndrome.

McKusick-Kaufman syndrome is a human developmental anomaly syndrome comprising mesoaxial or postaxial polydactyly, congenital heart disease and hydrometrocolpos. This syndrome is diagnosed most frequently in the Old Order Amish population and is inherited in an autosomal recessive pattern with reduced penetrance and variable expressivity. Homozygosity mapping and linkage analyses were conducted using two pedigrees derived from a larger pedigree published in 1978. The PedHunter software query system was used on the Amish Genealogy Database to correct the previous pedigree, derive a minimal pedigree connecting those affected sibships that are in the database and determine the most recent common ancestors of the affected persons. Whole genome short tandem repeat polymorphism (STRP) screening showed homozygosity in 20p12, between D20S162 and D20S894 , an area that includes the Alagille syndrome critical region. The peak two-point LOD score was 3.33, and the peak three-point LOD score was 5.21. The physical map of this region has been defined, and additional polymorphic markers have been isolated. The region includes several genes and expressed sequence tags (ESTs), including the jagged1 gene that recently has been shown to be haploinsufficient in the Alagille syndrome. Sequencing of jagged1 in two unrelated individuals affected with McKusick-Kaufman syndrome has not revealed any disease-causing mutations.

Abnormalities, Multiple↗
PubMed1998

Identification of a mutation in liver glycogen phosphorylase in glycogen storage disease type VI.

Glycogen storage disease type VI (GSD6) defines a group of disorders that cause hepatomegaly and hypoglycemia with reduced liver phosphorylase activity. The course of these disorders is generally mild, but definitive diagnosis requires invasive procedures. We analyzed a Mennonite kindred with an autosomal recessive form of GSD6 to determine the molecular defect and develop a non-invasive diagnostic test. Linkage analysis was performed using genetic markers flanking the liver glycogen phosphorylase gene ( PYGL ), which was suspected to be the cause of the disorder on biochemical grounds. Mennonite GSD6 was linked to the PYGL locus with a multipoint LOD score of 4.7. The PYGL gene was analyzed for mutations by sequencing genomic DNA. Sequencing of genomic DNA revealed a splice site abnormality of the intron 13 splice donor. Confirmation of the genomic mutation was performed by sequencing RT-PCR products, which showed heterogeneous PYGL mRNA lacking all or part of exon 13 in affected persons. This study is the first to demonstrate that a mutation in the PYGL gene can cause GSD6. This mutation is estimated to be present on 3% of Mennonite chromosomes and the disease affects 0.1% of that population. Determination of this mutation provides a basis for the development of a simple and non-invasive diagnostic test for the disease and the carrier state in this population and confirms biochemical data showing the importance of this gene in glucose homeostasis.

Base Sequence↗
PubMed1998

Software for constructing and verifying pedigrees within large genealogies and an application to the Old Order Amish of Lancaster County.

This paper describes PedHunter, a software package that facilitates creation and verification of pedigrees within large genealogies. A frequent problem in medical genetics is to connect distant relatives with a pedigree. PedHunter uses methods from graph theory to solve two versions of the pedigree connection problem for genealogies as well as other pedigree analysis problems. The pedigrees are produced by PedHunter as files in LINKAGE format ready for linkage analysis. PedHunter uses a relational database of genealogy data, with tables in specified format, for all calculations. The functionality and utility of PedHunter are illustrated by examples using the Amish Genealogy Database (AGDB), which was created for the Old Order Amish community of Lancaster County, Pennsylvania.

Christianity↗
PubMed1997

Prevalence of Pro250Arg mutation of fibroblast growth factor receptor 3 in coronal craniosynostosis.

BACKGROUND: The C749G (Pro250Arg) mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) has been found in patients with various types of craniosynostosis. We aimed to find out the proportion of cases of apparently non-syndromic coronal craniosynostosis attributable to this mutation. METHODS: We studied 26 patients with coronal craniosynostosis but no syndromic diagnosis, who were referred to a supra-regional specialist centre. Genomic DNA was analysed by PCR and restriction-enzyme digestion to identify the C749G mutation in FGFR3. Family members of patients found to have the mutation were also tested. FINDINGS: Eight (31%) of the 26 probands were heterozygous for the C749G mutation. In two cases, the mutation showed autosomal dominant transmission with evidence of variable expressivity; the remaining six cases were sporadic. We demonstrated in six families that the mutation had arisen de novo from clinically unaffected parents. INTERPRETATION: The C749G mutation in FGFR3 is a frequent cause of apparently non-syndromic coronal craniosynostosis. Our finding will aid genetic counselling and prenatal diagnosis. The mutation rate at this nucleotide is one of the highest described in the human genome.

Child, Preschool↗
PubMed1997

Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21.

Ecm1, the mouse gene encoding extracellular matrix protein 1, is highly expressed in bone and cartilage as well as in osteogenic, preosteoblastic and chondroblastic cell lines. Ecm1 was recently localized to a chromosomal region in mouse syntenic to human chromosome 1q21, establishing this gene as a prime candidate gene for pycnodysostosis, a rare, autosomal recessive sclerosing skeletal dysplasia. Shortly thereafter, it was determined that cathepsin K is the pycnodysostosis gene. We now report the radiation hybrid mapping of human ECM1 to 1q21, and the gene structure and coding sequence of human ECM1.

Amino Acid Sequence↗
PubMed1997

Fine mapping of the nail-patella syndrome locus at 9q34.

Nail-patella syndrome (NPS), or onychoosteodysplasia, is an autosomal dominant, pleiotropic disorder characterized by nail dysplasia, absent or hypoplastic patellae, iliac horns, and nephropathy. Previous studies have demonstrated linkage of the nail-patella locus to the ABO and adenylate kinase loci on human chromosome 9q34. As a first step toward isolating the NPS gene, we present linkage analysis with 13 polymorphic markers in five families with a total of 69 affected persons. Two-point linkage analysis with the program MLINK showed tight linkage of NPS and the anonymous markers D9S112 (LOD = 27.0; theta = .00) and D9S315 (LOD = 22.0; theta = .00). Informative recombination events place the NPS locus within a 1-2-cM interval between D9S60 and the adenylate kinase gene (AK1).

Chromosome Mapping↗