Retinal degeneration associated with RDH12 mutations results from decreased 11-cis retinal synthesis due to disruption of the visual cycle

Human Molecular Genetics     

Linkage analysis in Usher syndrome type I (USH1) families from Spain.

Usher syndrome (USH) is an autosomal recessive hereditary disorder characterised by congenital sensorineural hearing loss and gradual visual impairment secondary to retinitis pigmentosa (RP). The disorder is clinically and genetically heterogeneous. With regard to Usher type I (USH1), several subtypes have been described, the most frequent being USH1B located on chromosome 11q13.5. Of 18 USH1 families studied by linkage analysis, 12 (67%) showed significant lod score values for locus D11S527 (Zmax=14.032, theta=0.000) situated on chromosome 11q. Our findings suggest considerable genetic heterogeneity in the Spanish USH1 population. It is important to note that one of our families linked to the USH1B locus shows interesting intrafamilial clinical variability. As regards the remaining six USH1 families, the linkage analysis did not provide conclusive data, although two of them show slight linkage to markers located on chromosome 3q (Zmax=1.880, theta=0.000 for D3S1279), the same location that had previously been assigned to some USH3 families.     

Identification of three novel mutations of the noggin gene in patients with fibrodysplasia ossificans progressiva

We report noggin mutations in three Spanish families with fibrodysplasia ossificans progressiva (FOP). The three propositi have typical FOP findings; in the first and third families the parents are unaffected, while in the second family the father is partially affected. DNA of the three propositi and their parents was screened by sequencing for mutations in the noggin gene (NOG). Sequencing indicated a G to C mutation at nucleotide 274 of the NOG gene in the first propositus, encoding for the G92R substitution at the peptide level; this first mutation is de novo, the corresponding change not being observed in parents. In the second propositus, a G to T mutation at nucleotide 271 encodes for the G91C substitution, transmitted in the corresponding family by the partially affected father. In the third propositus, sequencing indicated a G to A mutation at nucleotide 275, encoding for the G92E substitution; this third mutation is de novo. All three mutations, as well as the Delta42 deletion already reported, resulted in the alteration of the portion of the NOG gene at positions 265-282, encoding for the potential N-myristoylation site at residues 89-GGGGGA-94.     

Vasculogenesis and angiogenesis in the subcardinal venous plexus of quail mesonephros: spatial and temporal morphological analysis

Vasculogenesis and angiogenesis are involved in a coordinated program for the development of the mesonephric subcardinal venous plexus of quail embryo. Vasculogenesis occurs between days 3 and 4 of incubation, while angiogenesis takes place from day 5 to day 7. Examination of vascular corrosion casts and whole mounts, and tissue sections labelled with specific markers to hemangioblast lineage (QH1, LEP100 and AcPase activity), allowed us to distinguish six phases in the formation of subcardinal plexus. (1) Appearance of isolated angioblast-like cells where the subcardinal plexus will form. (2) Alignment of angioblast-like cells into cellular strands. (3) Formation of compact vascular cords by association of angioblast-like strands. (4) Polygonal interconnection of vascular cords to constitute the primary subcardinal plexus. In this stage, isolated angioblast-like cells were present inside inter-vascular spaces. (5) The splitting of primary inter-vascular spaces by angiogenic sprouts to form secondary subcardinal plexus (outward angiogenesis). Isolated angioblast-like cells were not present in this stage. (6) Expansion of the secondary subcardinal plexus by insertion of slender transcapillary tissue pillars (inward angiogenesis) and angiogenic sprouts. We also describe three morphogenetic gradients during the development of the subcardinal plexus: ventral-to-dorsal, cranial-to-caudal and lateral-to-medial. Accepted: 9 November 2001     

Identification of bovine IgG as a major cross-reactive vertebrate meat allergen

BACKGROUND: Although beef is a main source of protein in Western diets, very little has been published on allergic reactions to beef or the main allergens implicated in these reactions. The aim was to evaluate the IgE antibody response to beef in suspected meat-allergic subjects and assess cross-reactivity of beef with other vertebrate meats. METHODS: Fifty-seven sera from suspected meat-allergic subjects were tested by grid blot for specific IgE antibodies to vertebrate meats (beef, lamb, pork, venison, and chicken), and the patterns of recognition of meat proteins were assessed by immunoblot studies. RESULTS: A 160-kDa band, identified as bovine IgG, was detected in raw beef in 83% (10/12) of beef-allergic subjects but in only 24% of the beef-tolerant subjects. IgE reactivity to a band of similar mol. mass was detected also in lamb and venison, but rarely in pork or chicken. Complete inhibition of the IgE reactivity to the bovine IgG was obtained with lamb, venison, and milk. IgE reactivity to this band also completely disappeared when beef or lamb extracts were separated under reducing conditions, indicating conformational epitopes. CONCLUSIONS: Bovine IgG appears to be a major cross-reacting meat allergen that could predict beef allergy. Further studies with oral IgG challenges should be performed to document the conclusion that in vitro reactivity correlates with clinical hypersensitivity. The role of bovine IgG in other bovine products such as milk, dander, or hair must also be studied, and the hypothesis that it is a cross-reacting allergen with other mammalian products validated.     

Fourteen novel OPA1 mutations in autosomal dominant optic atrophy including two de novo mutations in sporadic optic atrophy

The OPA1 gene, encoding a dynamin-related GTPase that plays a role in mitochondrial biogenesis, is implicated in most cases of autosomal dominant optic atrophy (ADOA). Sixty-nine pathogenic OPA1 mutations have been reported so far. Most of these are truncating mutations located in the GTPase domain coding region (exons 8-16) and at the 3'-end (exons 27-28). We screened 44 patients with typical ADOA using PCR-sequencing. We also tested 20 sporadic cases of bilateral optic atrophy compatible with ADOA. Of the 18 OPA1 mutations found, 14 have never been previously reported. The novel mutations include one nonsense mutation, 3 missense mutations, 6 deletions, one insertion and 3 exon-skipping mutations. Two of these are de novo mutations, which were found in 2 patients with sporadic optic atrophy. The recurrent c.2708_2711delTTAG mutation was found in 2 patients with a severe congenital presentation of the disease. These results suggest that screening for OPA1 gene mutations may be useful for patients with optic atrophy who have no affected relatives, or when the presentation of the disease is atypical as in the case of early onset optic atrophy.