ADAMTSL4-associated isolated ectopia lentis: Further patients, novel mutations and a detailed phenotype description

ADAMTSL4 mutations seem to be the most common cause of isolated ectoplia lentis (EL) and thus are important concerning the differential diagnosis of connective tissue syndromes with EL as main feature. In this study, we describe an additional cohort of patients with apparently isolated EL. All underwent a detailed clinical exam with cardiac evaluation combined with ADAMTSL4 mutation analysis. Mutations were identified in 12/15 patients with EL. Besides the European founder mutation p. (Gln256Profs*38) we identified five further mutations not yet described in the literature: p. (Leu249Tyrfs*21), p. (Ala388Glyfs*8), p. (Arg746His), p. (Gly592Ser), and p. (Arg865His). Clinical evaluation showed common additional ocular features such as high myopia, but no major systemic findings. In particular: no dilatation of the aortic root was reported on. This report increases the total number of patients with ADAMTSL4 mutations reported on today and reviews in detail the clinical findings in all patients reported on to date demonstrate, that these patients have a mainly ocular phenotype. There are no consistent systemic findings. The differentiation between syndromic and isolated EL is crucial for the further surveillance, treatment, and counseling of these patients, especially in young childre

A defect in the inner kinetochore protein CENPT causes a new syndrome of severe growth failure

Primordial growth failure has been linked to defects in the biology of cell division and replication. The complex processes involved in microtubule spindle formation, organization and function have emerged as a dominant patho-mechanism in these conditions. The majority of reported disease genes encode for centrosome and centriole proteins, leaving kinetochore proteins by which the spindle apparatus interacts with the chromosomes largely unaccounted for. We report a novel disease gene encoding the constitutive inner kinetochore member CENPT, which is involved in kinetochore targeting and assembly, resulting in severe growth failure in two siblings of a consanguineous family. We herein present studies on the molecular and cellular mechanisms that explain how genetic mutations in this gene lead to primordial growth failure. In both, affected human cell lines and a zebrafish knock-down model of Cenpt, we observed aberrations in cell division with abnormal accumulation of micronuclei and of nuclei with increased DNA content arising from incomplete and/or irregular chromosomal segregation. Our studies underscore the critical importance of kinetochore function for overall body growth and provide new insight into the cellular mechanisms implicated in the spectrum of these severe growth disorders

Cellular aberrations in patient fibroblast lines.

<p>(A) Immunofluorescence staining of immortalized fibroblasts of index IA; blue—DAPI; magenta—CENPT; green—CENPA or phosphorylated CENPA. Scale bars represent 10μm. Multinucleated cells are depicted in columns 1–3. Micronuclei (solid arrowheads) and chromosome lagging (arrow). (B) Normal mitosis on the left. Examples of multipolar mitosis on the right in immortalized fibroblast of index IA. Blue—DAPI; magenta—CENPT; green–γ-tubulin. Scale bars represent 10μm.</p

Cell size distribution.

<p>(A) Nuclear size distribution and CENPT signal intensity in immortalized fibroblasts measured by immunofluorescence. CENPT signal intensities are age-corrected. (B) Right-shifted histograms of patient (red) and parent (blue) EBV-transformed lymphoblast cell lines in relation to three different controls (green) by flow cytometry staining. Propidium iodide was used as DNA stain.</p

Knock-down zebrafish model.

<p>(A) Comparison of morpholino target effects at 24hpf and localization of morpholino targets in relation to the zebrafish <i>cenpt</i> gene and the conserved histone-fold domain (HFD, green box). (B) Effect of Mo8 (Mo8/8) on transcription of zebrafish <i>cenpt</i> in comparison to control morpholino (CoMo). (C) Dose response curve of Mo12 (Mo12/12) at 75hpf. On the bottom RT-PCR of Mo12 dose response curve. The upper band represents the wild-type band. (D) Head and eye measurements in Mo12 injected zebrafish at 48hpf. (E) Left panel shows a normal mitosis. The three right panels are examples of mitotic aberrations seen in Mo12 injected Tg(h2afv:GFP) zebrafish live imaging. (F) Time lapse of aberrant mitosis in Mo12 injected Tg(h2afv:GFP) zebrafish.</p

Finlands balance of payments for 1973 and 1974

Suomen virallinen tilasto (SVT