Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1.

Megaloblastic anaemia 1 (MGA1, OMIM 261100) is a rare, autosomal recessive disorder characterized by juvenile megaloblastic anaemia, as well as neurological symptoms that may be the only manifestations. At the cellular level, MGA1 is characterized by selective intestinal vitamin B12 (B12, cobalamin) malabsorption. MGA1 occurs worldwide, but its prevalence is higher in several Middle Eastern countries and Norway, and highest in Finland (0.8/100,000). We previously mapped the MGA1 locus by linkage analysis in Finnish and Norwegian families to a 6-cM region on chromosome 10p12.1 (ref. 8). A functional candidate gene encoding the intrinsic factor (IF)-B12 receptor, cubilin, was recently cloned; the human homologue, CUBN, was mapped to the same region. We have now refined the MGA1 region by linkage disequilibrium (LD) mapping, fine-mapped CUBN and identified two independent disease-specific CUBN mutations in 17 Finnish MGA1 families. Our genetic and molecular data indicate that mutations in CUBN cause MGA1.

A molecular orbital investigation of the conformation of transfer RNA.

The PCILO method has been used for a theoretical exploration of the conformational properties of tRNAPhe with respect to the phosphodiester torsion angles. The computations were based on the utilisation of the dinucleoside triphosphate model and took into account the different combinations of sugar puckers and different conformations about the C4'-C5' bond. The dependence of the (omega'-omega) conformational energy maps upon these factors was specified. A detailed comparison is carried out between the theoretical results and experimental data on the crystal structure of tRNAPhe produced by four different groups of investigators.

[Typical tripeptide sequences of collagen: quantitative conformation study]. / Séquences tripeptidiques typiques du collagène: étude conformationnelle quantique.

Theoretical and experimental investigations on the conformations of synthetic polytripeptides, with Gly-R2-R3 general repetitive sequence, are of great interest for the comprehension of the factors which contribute to the triple helix stabilization. Using appropriate molecules as models, we have investigated by the PCILO method the intrinsic conformational possibilities of each "in situ" residue for the following cases : Gly-imino-imino, Gly-amino-imino and Gly-imino-amino which represent the most important sequences occurring in the primary structure of collagen. The computations were carried out taking into account the two pyrrolidine ring puckerings and the preferential side-chains orientations. Extending our previous work concerning the isomeric polytripripeptides Gly-X-Pro and Gly-Pro-X with X epsilon (Pro, Phe) we have studied the cases of X epsilon (Ala, Ser). In this brief communication, we present a preliminary synthesis of these recent results.

Quantum molecular modeling of the interaction between guanine and alkylating agents--1--sulfur mustard.

Interaction between Guanine and the episulfonium form of Sulfur mustard (HD) was studied using the ab initio LCAO-MO method at the HF/6-31G level. The alkylation mechanism on guanine-N7 was analyzed by using a supermolecular modeling. Our stereostructural results associated with the molecular electrostatic potentials and HOMO-LUMO properties, show that in vacuum the alkylation of the N7 of guanine by HD in the aggressive episulfonium form is a direct process without transition state and of which the pathway is determined.

Quantum molecular modeling of the interaction between guanine and alkylating agents--2--nitrogen mustard.

The alkylation mechanism of guanine by nitrogen mustard (HN2) was studied by using a supermolecular modeling at the ab initio 6-31G level. Our computations show that interaction of guanine with the aziridinium form of HN2 necessitates a transition state for the N7 alkylation route. The pathway of N7-guanine alkylation by nitrogen and sulfur mustards is discussed on the basis of the Molecular Electrostatic Potential and HOMO-LUMO properties of these molecules.

Quantum molecular modeling of the elastinic tetrapeptide Val-Pro-Gly-Gly.

The free Val-Pro-Gly-Gly tetrapeptide belonging to the Proline-rich sequences of elastin has been studied both theoretically and experimentally. The molecular modelisation was carried out using AM1 and ab initio quantum computations while the conformation in solution was ascertained by circular dichroism spectroscopy performed on the synthesized tetrapeptide. Experimental and theoretical investigations lead to the conclusion that the most probable structure is constituted by a type II beta-turn.

[A changing panorama of cerebral palsy? A population-based study of children born during the 20-year period 1970-89]. / Et endret panorama av cerebral parese? En populasjonsbasert underslkelse av barn fldt i 20-årsperioden 1970-89.

In a population-based study cerebral palsy was diagnosed in 110 cases (2.4 per 1,000) among live born children with birth weight > or = 500 g (N = 45,976) during the 20-year period 1970-89 (cerebral palsy cases with a postneonatal etiology excluded). The incidence of cerebral palsy showed a linear declining trend from 2.8 per 1,000 in the first five-year cohort born 1970-74 to 2.0 per 1,000 in children born 1985-89 (p = 0.17). 15.9% of the decline in incidence of cerebral palsy from the first to the second ten-year cohort could be explained by a decreasing rate of low birth weight (500-2,499 g) in the population, from 4.2% 1970-79 to 3.8% 1980-89 (p < 0.05). The neonatal mortality rate declined significantly from 7.2 per 1,000 in the first to 3.9 per 1,000 in the last ten-year cohort respectively (p < 0.01). More children with cerebral palsy born in the ten-year period 1980-89 were treated with mechanical ventilation in the neonatal period (13/46; 28.3%) than such children born in the ten-year period 1970-79 (4/64; 6.3%) (p < 0.01). The results contrast with the traditional findings of a higher incidence of cerebral palsy incidence following improved survival of infants with low birth weight. Our results may reflect a more integrated development of perinatal care. Research on ways of preventing low birth weight may allow us to lower the incidence of cerebral palsy still further.

A changing pattern of cerebral palsy. Declining trend for incidence of cerebral palsy in the 20-year period 1970-89.

In a population-based study cerebral palsy (CP) was diagnosed in 110 cases (2.4 per 1000) among children live born with birth weight > or = 500 g (n = 45,976) during the 20-year-period 1970-89 (CP cases with a postneonatal etiology excluded). The CP-incidence showed a linear trend of decline from 2.8 per 1,000 in the first 5-year-cohort born 1970-74, to 2.0 per 1,000 in children born 1985-89 (p = 0.17). Birth weight specific CP-incidence showed a trend of decline in very low birth weight infants (500-1,499 g) and in infants > or = 2,500 g from the first 10-year-cohort born 1970-79 to the second born 1980-89. The same trend occurred for the incidence of spastic diplegia in total and in children born preterm. These trends of decline did not achieve statistical significance (p > 0.05). The CP-incidence was 36.7 and 11.3 times higher among infants with birth weight 500-1,499 g and 1,500-2,499 g respectively compared to infants > or = 2,500 g (p < 0.01). 15.9% of the decline in CP-incidence from the first to the second 10-year-cohort could be explained by a decreased low birth weight rate (500-2,499 g) in the population, from 4.2% 1970-79 to 3.8% 1980-89 (p < 0.05). The origin of CP was considered prenatal in 22 (20%), perinatal in 47 (42.7%), and undifferentiated in 41 (37.3%) of the cases. More CP-children born in the 10-year-period 1980-89 were treated with mechanical ventilation in the neonatal period (13/46; 28.3%) than those born in the 10-year-period 1970-79 (4/64; 6.3%) (p < 0.01). The neonatal mortality rate declined significantly from 7.2 per 1,000 in the first to 3.9 per 1,000 in the last 10-year-cohort respectively (p < 0.01). Birth weight-specific neonatal mortality rates declined more than 50% in all weight groups (p < 0.01). The results are contradictive to other investigations showing increased CP-incidence following improved survival rates in low birth weight infants, and may reflect a different pattern for development of perinatal care (organization, intensive care). The overall effect of mechanical ventilation may be improved survival and prevention of brain damage, though the percentage of ventilated CP-children increased. Preventing low birth weight should be a main strategy for preventing CP.

[Cerebral palsy as indicator of quality of neonatal care]. / Cerebral parese som nyfødtmedisinsk kvalitetsindikator.

BACKGROUND: An investigation of the prevalence of cerebral palsy in relation to neonatal intensive care. MATERIAL AND METHODS: Population based study in live-born children with birthweight > or = 500 g in the Norwegian county of Vestfold over the 25-year period 1970-94 (n = 58,448). Retrospective and prospective control of cases (cases with a postneonatal origin of cerebral palsy excluded) with a minimum follow-up to four years of age. RESULTS: Cerebral palsy was diagnosed in 139 cases (2.4 per 1,000). The prevalence declined from 2.8 per 1,000 in the first five-year cohort born 1970-74, to 2.2 per 1,000 in children born in each of the three five-year cohorts born 1980-84, 1985-89, and 1990-94 (p = 0.24). The neonatal mortality rate declined significantly from 8.7 per 1,000 in the first to 2.8 per 1,000 in the last five-year cohort (p < 0.0001). The low birthweight (500-2,499 g) rate in live-born infants increased significantly in 1990-94 compared to 1985-89 (4.5% vs 3.9% respectively; p < 0.05). After a local ventilator treatment programme (operative from 1989) was established, transports of infants with severe respiratory distress syndrome to the regional hospital declined from 3 per 1,000 live-born infants to 1 per 1,000 (p < 0.0001). INTERPRETATION: A decentralised neonatal intensive care programme can be developed, with substantial decline in neonatal mortality without a corresponding increase in cerebral palsy prevalence.

Conformational and electrostatic properties of V-G-G-V-G, a typical sequence of the glycine-rich regions of elastin. An ab initio quantum molecular study.

The conformational analysis and electrostatic properties of the monomeric sequence V-G-G-V-G of the glycine-rich regions of elastin is presented with the aim of explaining NMR and CD experimental results. On the basis of the molecular model NH+3-V-G-G-V-G-COO, Gaussian 92 quantum-molecular computations were performed by using principally an ab initio method at the 3-21G level and AM1. The occurrence of local secondary structures and of beta I, beta II, beta II' and VIa turns is discussed. Our results clearly demonstrate that the transconformations beta I-->half turn (which was invoked to explain experimental results) and beta I-->beta II' are theoretically allowed.

Conformational studies on polypeptide models of collagen. Poly(Gly-Pro-Val), poly(Gly-Pro-Met), poly(Gly-Val-Pro) and poly(Gly-Met-Pro).

The title polytripeptides were synthesized and studied experimentally, by circular dichroism, and theoretically, by quantum mechanical methods. With the exception of poly(Gly-Pro-Val), which was found to be essentially structureless in solution, the other polymers adopt folded conformations, most probably of type II beta-bends. Conclusions from theoretical studies were generally in agreement with the experimental results. In particular, it is noteworthy that the optimized (phi, psi) maps for poly(Gly-Pro-Met) showed the absolute minimum (phi = 60 degree, psi = 0 degrees) located inside the beta II bend space.

Selective intestinal malabsorption of vitamin B12 displays recessive mendelian inheritance: assignment of a locus to chromosome 10 by linkage.

Juvenile megaloblastic anemia caused by selective intestinal malabsorption of vitamin B12 has been considered a distinct condition displaying autosomal recessive inheritance. It appears to have a worldwide distribution, and comparatively high incidences were reported 30 years ago in Finland and Norway. More recently, the Mendelian inheritance of the condition has been questioned because almost no new cases have occurred in these populations. Here we report linkage studies assigning a recessive-gene locus for the disease to chromosome 10 in previously diagnosed multiplex families from Finland and Norway, proving the Mendelian mode of inheritance. The locus is tentatively assigned to the 6-cM interval between markers D10S548 and D10S466, with a multipoint maximum lod score (Zmax) of 5.36 near marker D10S1477. By haplotype analysis, the healthy sibs in these families did not appear to constitute any examples of nonpenetrance. We hypothesize that the paucity of new cases in these populations is due either to a dietary effect on the gene penetrance that has changed with time, or to a drop in the birth rate in subpopulations showing enrichment of the mutation, or to both of these causes.

Imerslund-Gräsbeck anemia. A long-term follow-up study.

A follow-up study has been performed on 14 patients, now aged 6-46 years, with Imerslund-Gräsbeck anemia (congenital, hereditary selective malasorption of vitamin B12). On intramuscular vitamin B12 therapy, the patients are clinically and hematologically normal. Those who had constant proteinuria in childhood continue to excrete protein in the urine. Our patients excrete an average of 750 mg of protein per 24 hours (range 13-1460 mg). The proteinuria is predominantly of glomerular origin, but some is also of tubular origin. Renal biopsies of the two oldest patients were normal on light microscopy. Electron microscopy revealed moderate signs of chronic glomerulopathy of mesangioproliferative type in both patients. The renal lesions do not seem to be progressive.

Experimental and theoretical conformational studies on polypeptide models of collagen. Poly(Gly-Pro-Ile) and poly(Gly-Ile-Pro).

The synthetic polytripeptides poly(Gly-Pro-Ile) and poly(Gly-Ile-Pro) were studied both experimentally (mainly by circular dichroism spectroscopy) and theoretically by quantum mechanical methods. Poly(Gly-Ile-Pro) adopts a collagen-like structure under favourable conditions while the isomeric poly(Gly-Pro-Ile) does not. Theoretical studies emphasize severe intrastrand interactions which limit the main chain conformations in the case of poly(Gly-Ile-Pro). On the other hand, both the side cahin and the backbone in poly(Gly-Pro-Ile) can take up many different local conformations. Therefore, it seems that the conformational behaviour of synthetic polytripeptides can be at least partially explained in terms of local interactions.

A new patient with hyperornithinaemia, hyperammonaemia and homocitrullinuria treated early with low protein diet.

The characteristic biochemical disturbances of the amino acid and pyrimidine metabolism are described and illustrated by the first case of the HHH syndrome reported in Norway. The disorder was treated with a low protein diet at an early age and the patient developed normally on this diet.