Apert syndrome, one of five craniosynostosis syndromes caused by allelic mutations of fibroblast growth-factor receptor 2 (FGFR2), is characterized by symmetrical bony syndactyly of the hands and feet. We have analyzed 260 unrelated patients, all but 2 of whom have missense mutations in exon 7, which affect a dipeptide in the linker region between the second and third immunoglobulin-like domains. Hence, the molecular mechanism of Apert syndrome is exquisitely specific. FGFR2 mutations in the remaining two patients are distinct in position and nature. Surprisingly, each patient harbors an Alu-element insertion of approximately 360 bp, in one case just upstream of exon 9 and in the other case within exon 9 itself. The insertions are likely to be pathological, because they have arisen de novo; in both cases this occurred on the paternal chromosome. FGFR2 is present in alternatively spliced isoforms characterized by either the IIIb (exon 8) or IIIc (exon 9) domains (keratinocyte growth-factor receptor [KGFR] and bacterially expressed kinase, respectively), which are differentially expressed in mouse limbs on embryonic day 13. Splicing of exon 9 was examined in RNA extracted from fibroblasts and keratinocytes from one patient with an Alu insertion and two patients with Pfeiffer syndrome who had nucleotide substitutions of the exon 9 acceptor splice site. Ectopic expression of KGFR in the fibroblast lines correlated with the severity of limb abnormalities. This provides the first genetic evidence that signaling through KGFR causes syndactyly in Apert syndrome.

The pathogenesis of diarrhea in intestinal inflammatory states is a multifactorial process involving the effects of inflammatory mediators on epithelial transport function. The effect of colonic inflammation on the gene expression of DRA (downregulated in adenoma), a chloride-sulfate anion transporter that is mutated in patients with congenital chloridorrhea, was examined in vivo as well as in an intestinal epithelial cell line. DRA mRNA expression was diminished five- to sevenfold in the HLA-B27/β2m transgenic rat compared with control. In situ hybridization showed that DRA, which is normally expressed in the upper crypt and surface epithelium of the colon, was dramatically reduced in the surface epithelium of the HLA-B27/β2m transgenic rat, the interleukin-10 (IL-10) knockout mouse with spontaneous colitis, and in patients with ulcerative colitis. Immunohistochemistry demonstrated that mRNA expression of DRA reflected that of protein expression in vivo. IL-1β reduced DRA mRNA expression in vitro by inhibiting gene transcription. The loss of transport function in the surface epithelium of the colon by attenuation of transporter gene expression, perhaps inhibited at the level of gene transcription by proinflammatory cytokines, may play a role in the pathogenesis of diarrhea in colitis.

Rice (Oryza sativa) is the worlds’ most important cereal and potentially an important source of zinc (Zn) for people who eat mainly rice. To improve Zn delivery by rice, plant Zn uptake and internal allocation need to be better understood. This study reports on within‐plant allocation and potential Zn accumulation in the rice grain in four so‐called aerobic rice cultivars (Handao297, K150, Handao502 and Baxiludao). Two controlled‐condition experiments were carried out, one with a wide range of constant Zn concentrations in the medium and one with a range of plant growth rate‐related supply rates. In both experiments, increased Zn supply induced increased plant Zn uptake rate throughout crop development, when expressed as daily Zn uptake (μg day−1) or as daily Zn uptake per gram of plant dry matter (μg g−1). Zinc mass concentration (ZnMC) in all plant organs increased with an increase in Zn supply but to various degrees. At higher uptake levels, the ZnMC in stems increased most, while the ZnMC in hulled grains (brown rice) increased least. The increase in leaf ZnMC was generally small, but at toxic levels in the medium, leaf ZnMC increased significantly. It appears that regulation of grain Zn loading differs from regulation of Zn loading to other organs. A milling test on seeds of Baxiludao and Handao502 showed that when ZnMC in brown rice increased from 13 to 45 mg kg−1, ZnMC in polished rice grains (endosperm) also increased from 9 to 37 mg kg−1 but remained three to five times lower than that in the bran. Irrespective of the ZnMC in the brown rice, around 75% of total grain Zn was present in the endosperm. In both cultivars, there was a major difference in ZnMC between bran and endosperm (120 and 37 mg kg−1, respectively), suggesting a barrier for Zn transport between the two tissues. There seems to be a second barrier between stem and rachis, as their ZnMCs also differed greatly (300 and 100 mg kg−1, respectively) in both cultivars at higher plant ZnMC. It is concluded that there is too little scope from a human nutrition perspective to enhance ZnMC in rice endosperm by simply increasing the Zn supply to rice plants because Zn allocation to the endosperm is limited, while observed genotypic differences indicate scope for improvement through breeding.

We investigated the uptake and distribution of zinc (Zn) either applied to the roots or to the leaves in rice during grain development. Plants of two aerobic rice cultivars were grown in a nutrient solution with either sufficient Zn or surplus Zn. Root treatment with 1 week's supply of both 65 Zn and unlabelled Zn was started at flowering or 15 days after flowering (DAF). Foliar treatment with 65 Zn applied to the flag leaf or to senescent leaves was carried out at flowering. When 65 Zn was applied to roots, plants continued to take up Zn after flowering, even beyond 15 DAF, irrespective of cultivar and Zn nutritional status of the plants. During the 1 week of supply of both 65 Zn and unlabelled Zn, which either started at flowering or 15 DAF, the absorbed 65 Zn was mainly distributed to roots, stem and grains. Little 65 Zn was allocated to the leaves. Following a week of 65 Zn supply directly after flowering, under sufficient Zn or surplus Zn, the proportions of total 65 Zn uptake allocated to the grains continued to change during grain filling (9-33%). This Zn mainly came from the roots but under sufficient Zn supply also from the stem. With 65 Zn applied to leaves (either the flag leaf or the lowest senescent leaf), both cultivars showed similar Zn distribution within the plants. About 45-50% of the 65 Zn absorbed was transported out of the 65 Zn-treated leaf. From that Zn, more than 90% was translocated to other vegetative organs; little was partitioned to the panicle parts and even less to the grains. These results suggest that in rice plants grown under sufficient or surplus Zn supply, most of the Zn accumulated in the grains originates from uptake by roots after flowering and not from Zn remobilisation from leaves.