Interstitial lung disease in children - genetic background and associated phenotypes

Interstitial lung disease in children represents a group of rare chronic respiratory disorders. There is growing evidence that mutations in the surfactant protein C gene play a role in the pathogenesis of certain forms of pediatric interstitial lung disease. Recently, mutations in the ABCA3 transporter were found as an underlying cause of fatal respiratory failure in neonates without surfactant protein B deficiency. Especially in familiar cases or in children of consanguineous parents, genetic diagnosis provides an useful tool to identify the underlying etiology of interstitial lung disease. The aim of this review is to summarize and to describe in detail the clinical features of hereditary interstitial lung disease in children. The knowledge of gene variants and associated phenotypes is crucial to identify relevant patients in clinical practice

YAC clone contigs surrounding the Zfx and Pola loci on the mouse X chromosome.

Pulsed-field mapping of a number of DNA markers in the Pola-Zfx region of the mouse X chromosome has established a genomic restriction map extending over 1.4 Mb. A number of YAC clones from the Pola-Zfx region have been isolated from three mouse YAC libraries--first, a mouse C57BL/10 partial R1 YAC library constructed in a yeast strain carrying a rad52 mutation (Chartier et al. (1992) Nature Genetics 1: 132-136); second, a mouse C3H partial R1 library (Larin et al. (1991) Proc. Natl. Acad. Sci. USA 88: 4123-4127); and third, a mouse C57BL/6 partial R1 library (Burke et al. (1991) Mamm. Genome 1:65). Six YAC clones encompass the Zfx-Pola region, confirming the linkage of the Pola and Zfx loci and establishing a physical map order in this region of cen-Pola-DXCrc140-DXCrc57-Zfx-tel. The close linkage of Pola and Zfx in the mouse genome suggests that the POLA and ZFX loci must also be closely linked on the human X chromosome

An integrated YAC-overlap and 'cosmid-pocket' map of the human chromosome 21.

We describe here the construction of an ordered clone map of human chromosome 21, based on the identification of ordered sets of YAC clones covering > 90% of the chromosome, and their use to identify groups of cosmid clones (cosmid pockets) localised to subregions defined by the YAC clone map. This is to our knowledge the highest resolution map of one human chromosome to date, localising 530 YAC clones covering both arms of the chromosome, spanning > 36 Mbp, and localising more than 6300 cosmids to 145 intervals on both arms of the chromosome. The YAC contigs have been formed by hybridising a 6.1 equivalents chromosome 21 enriched YAC collection displayed on arrayed nylon membranes to a series of 115 DNA markers and Alu-PCR products from YACs. Forty eight mega-YACs from the previously published CEPH-Genethon map of sequence tagged sites (STS) have also been included in the contig building experiments. A YAC tiling path was then size-measured and confirmed by gel-fingerprinting. A minimal tiling path of 70 YACs were then used as probes against the 7.5 genome equivalents flow sorted chromosome 21 cosmid library in order to identify the lists of cosmids mapping to alternating shared--non-shared intervals between overlapping YACs ('cosmid pockets'). For approximately 1/5 of the minimal tiling path of YACs, locations and non-chimaerism have been confirmed by fluorescence in situ hybridisation (FISH), and approximately 1/5 of all cosmid pocket assignments have independent, confirmatory marker hybridizations in the ICRF cosmid reference library system. We also demonstrate that 'pockets' contain overlapping sets of cosmids (cosmid contigs). In addition to being an important logical intermediate step between the YAC maps published so far and a future map of completely ordered cosmids, this map provides immediately available low-complexity cosmid material for high resolution FISH mapping of chromosomal aberrations on interphase nuclei, and for rapid positional isolation of transcripts in the highly resolved regions of genetic interest

Identification of YAC and cosmid clones encompassing the ZFX-POLA region using irradiation hybrid cell lines.

The human Xp21.3-p22.1 region is poorly mapped relative to other X chromosome regions. To target cosmid and YAC clones specifically from Xp21.3-p22.1 for rapid contig construction, a hybridization-based screening approach using irradiation hybrids has been used. Alu-PCR products generated from hybrid lines containing small overlapping fragments from Xp21-p22 were hybridized to an X chromosome cosmid library, and cosmids predicted by their hybridization pattern to map to the region of interest were analyzed by fluorescence in situ hybridization (FISH). Hybridization of the cosmids in pools to gridded YAC libraries identified 15 YACs, which were verified and tested for chimerism by FISH. Cosmid content analysis of the YACs defined two contigs, one with 12 YACs covering about 1.5 Mb and one with 3 YACs. Five YACs from the 12-YAC cluster had been previously recognized by DNA polymerase alpha (POLA). ZFX identified a single YAC; hence, the physical linkage of ZFX and POLA was demonstrated within the contig. Four YACs had been isolated previously with ZFX and these extend the contig to 2 Mb. Restriction mapping of several YACs demonstrates that ZFX and POLA are about 700 kb apart, a distance similar to that reported in the mouse between Zfx and Pola. The order of these two loci and two additional loci identified by homologous mouse linking clones was found to be conserved between human and mouse: tel-ZFX-DXCrc57-DXCrc140-POLA-cen. We have shown that YAC contigs can be rapidly constructed from targeted regions without the need for time-consuming YAC end rescue and chromosomal walking.(ABSTRACT TRUNCATED AT 250 WORDS

Narrowing inequalities in infant mortality in Southern Brazil Redução das desigualdades na mortalidade infantil na região Sul do Brasil

OBJECTIVE: To determine the trends of infant mortality from 1995 to 1999 according to a geographic area-based measure of maternal education in Porto Alegre, Brazil. METHODS: A registry-based study was carried out and a municipal database created in 1994 was used. All live births (n=119,170) and infant deaths (n=1,934) were considered. Five different geographic areas were defined according to quintiles of the percentage of low maternal educational level (<6 years of schooling): high, medium high, medium, medium low, and low. The chi-square test for trend was used to compare rates between years. Incidence rate ratio was calculated using Poisson regression to identify excess infant mortality in poorer areas compared to higher schooling areas. RESULTS: The infant mortality rate (IMR) decreased steadily from 18.38 deaths per 1,000 live births in 1995 to 12.21 in 1999 (chi-square for trend p<0.001). Both neonatal and post-neonatal mortality rates decreased although the drop seemed to be steeper for the post-neonatal component. The higher decline was seen in poorer areas. CONCLUSION: Inequalities in IMR seem to have decreased due to a steeper reduction in both neonatal and post-neonatal components of infant mortality in lower maternal schooling area.<br>OBJETIVO: Determinar as tendências da mortalidade infantil de 1995 a 1999, segundo a escolaridade materna, medidas em base geográfica, em Porto Alegre, Brasil. MÉTODOS: Estudo baseado em dados secundários de um banco de dados municipal, criado em 1994. Todos os nascidos vivos (119.170 nascimentos) e óbitos infantis (1.934 óbitos) foram considerados. Foram definidas cinco diferentes áreas geográficas segundo os quintis de percentagem de escolaridade materna baixa (menos de seis anos de estudo): alta, médio-alta, média, média-baixa e baixa escolaridade. Foi usado o teste do qui-quadrado para tendências de comparação das taxas entre as áreas. Foi calculada a razão de incidências pela regressão de Poisson para identificar excesso de mortalidade infantil nas áreas mais pobres, em comparação com as mais ricas. RESULTADOS: A taxa de mortalidade infantil decresceu de 18,38 por 1.000 nascidos vivos em 1995 e para 12,21 em 1999 (qui-quadrado para tendência p<0,001). Ambos os componentes neonatal e pós-neonatal foram reduzidos, embora a queda pareceu ser mais intensa no componente pós-neonatal. A maior redução foi observada nas áreas mais pobres. CONCLUSÃO: a redução nos componentes de mortalidade neonatal e pós-neonatal em área de mais baixa escolaridade materna