Hereditary pancreatitis (HP) is a rare, early-onset genetic disorder characterized by epigastric pain and often more serious complications. We now report that an Arg–His substitution at residue 117 of the cationic trypsinogen gene is associated with the HP phenotype. This mutation was observed in all HP affected individuals and obligate carriers from five kindreds, but not in individuals who married into the families nor in 140 unrelated individuals. X-ray crystal structure analysis, molecular modelling, and protein digest data indicate that the Arg 117 residue is a trypsin-sensitive site. Cleavage at this site is probably part of a fail-safe mechanism by which trypsin, which is activated within the pancreas, may be inactivated; loss of this cleavage site would permit autodigestion resulting in pancreatitis.

Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.

Over the last decade the identification of mutations in the receptors for fibroblast growth factors (FGFs) has defined essential roles for FGF signaling in both endochondral and intramembranous bone development. FGF signaling pathways are essential for the earliest stages of limb development and throughout skeletal development. In this review, we examine the role of FGF signaling in bone development and in human genetic diseases that affect bone development. We also explore what is presently known about how FGF signaling pathways interact with other major signaling pathways that regulate chondrogenesis and osteogenesis. Overview of skeletal development Skeletal elements are formed through two distinct developmental processes. Endochondral ossification gives rise to long bones that comprise the appendicular skeleton, facial bones, vertebrae, and the lateral medial clavicles. Intramembranous ossification gives rise to the flat bones that comprise the cranium and medial clavicles. Both types of ossification involve an initial condensation of mesenchyme and the eventual formation of calcified bone. However, intramembranous bone formation accomplishes this directly, whereas endochondral ossification incorporates an intermediate step in which a cartilaginous template regulates the growth and patterning of the developing skeletal element. Development of endochondral bones initiates shortly after the formation of the limb bud with the condensation of loose mesenchyme, marked by expression of type

/pdf/fgf-signaling-pathways-in-endochondral-and-intramembranous-1ju3vm24l9.pdf

FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.

Moraxella catarrhalis (formerly known as Branhamella catarrhalis) has
 emerged as a significant bacterial pathogen of humans over the past two
 decades. During this period, microbiological and molecular diagnostic
 techniques have been developed and improved for M. catarrhalis, allowing
 the adequate determination and taxonomic positioning of this pathogen.
 Over the same period, studies have revealed its involvement in respiratory
 (e.g., sinusitis, otitis media, bronchitis, and pneumonia) and ocular
 infections in children and in laryngitis, bronchitis, and pneumonia in
 adults. The development of (molecular) epidemiological tools has enabled
 the national and international distribution of M. catarrhalis strains to
 be established, and has allowed the monitoring of nosocomial infections
 and the dynamics of carriage. Indeed, such monitoring has revealed an
 increasing number of B-lactamase-positive M. catarrhalis isolates (now
 well above 90%), underscoring the pathogenic potential of this organism.
 Although a number of putative M. catarrhalis virulence factors have been
 identified and described in detail, their relationship to actual bacterial
 adhesion, invasion, complement resistance, etc. (and ultimately their role
 in infection and immunity), has been established in a only few cases. In
 the past 10 years, various animal models for the study of M. catarrhalis
 pathogenicity have been described, although not all of these models are
 equally suitable for the study of human infection. Techniques involving
 the molecular manipulation of M. catarrhalis genes and antigens are also
 advancing our knowledge of the host response to and pathogenesis of this
 bacterial species in humans, as well as providing insights into possible
 vaccine candidates. This review aims to outline our current knowledge of
 M. catarrhalis, an organism that has evolved from an emerging to a
 well-established human pathogen.

/pdf/moraxella-catarrhalis-from-emerging-to-established-pathogen-nvju43cf6i.pdf

Moraxella catarrhalis: from Emerging to Established Pathogen

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. (Endocrine Reviews 21: 23‐39, 2000)

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.

During the last few years, it has been demonstrated that some syndromic craniosynostosis and short-limb dwarfism syndromes, a heterogeneous group comprising of 11 distinct clinical entities, are caused by mutations in one of three fibroblast growth factor receptor genes (FGFR1, FGFR2, and FGFR3). The present review list all mutations described to date in these three genes and the phenotypes associated with them. In addition, the tentative phenotype-genotype correlation is discussed, including the most suggested causative mechanisms for these conditions.

Clinical spectrum of fibroblast growth factor receptor mutations.

Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes.

Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson—Weiss syndrome

Development and validation of a multiplex PCR-based assay for the upper respiratory tract bacterial pathogens haemophilus influenzae, streptococcus pneumoniae, and moraxella catarrhalis

Recent studies using the polymerase chain reaction (PCR) have identified bacterial and viral genomic sequences in culture-negative pediatric middle ear effusions. To evaluate this technique in adults, 19 effusions were analyzed to compare bacterial and viral culture and PCR detection of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and adenovirus. Effusions from 4 subjects positive for human immunodeficiency virus (HIV) were analyzed by PCR for HIV virus. Three of 19 effusions were culture-positive for bacteria, and 0 of 19 for viruses. Fifteen of 19 effusions were PCR-positive for bacterial genomic sequences, and 0 of 19 for adenovirus. Thirteen of 15 PCR-positive specimens demonstrated S pneumoniae, 5 of 15 H influenzae, and 0 of 13 M catarrhalis. All 4 effusions from HIV-positive subjects were PCR-positive for HIV. No effusion was culture-positive and PCR-negative. These results confirm that culture-negative middle ear effusions contain genomic sequences from bacterial pathogens. Finding of HIV RNA and DNA in effusion from HIV-positives suggests replicating virus in this fluid.

Analysis of adult otitis media: polymerase chain reaction versus culture for bacteria and viruses.

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Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson—Weiss syndrome

Development and validation of a multiplex PCR-based assay for the upper respiratory tract bacterial pathogens haemophilus influenzae, streptococcus pneumoniae, and moraxella catarrhalis

Analysis of adult otitis media: polymerase chain reaction versus culture for bacteria and viruses.