Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).
Cells of Dictyostelium discoideum respond chemotactically to.cyclic AMP [l] and to folic acid [3]. Cyclic AMP is a most efficient attractant for cells of the aggregation phase [2], folic acid is more effective with preaggregation cells [4]. Both cyclic AMP and folic acid stimulate also cell development from the preaggregation phase to the aggregation competent state [S-8]. During this process the cells acquire the capacity to synthesize cyclic AMP periodically, and to release it into the extracellular space in form of pulses [9] . The administration of cyclic AMP or folic acid pulses accelerates the onset of sustained oscillations [5,8] .The cyclic-AMP induced responses are known to be mediated by cell-surface receptors [lo-121. The intermediate steps in signal processing from the receptors to the various intracellular targets are unknown. In the present communication we show that upon stimulation of early preaggregation cells with folic acid a rapid increase of the cyclic GMP concentration is induced. A biphasic increase of cyclic GMP is observed in late preaggregation cells stimulated by cyclic AMP. The second cyclic GMP peak is succeeded by a cyclic AMP peak known to be based on the activation of adenylate cyclase [ 131. Free-running oscillations of cyclic GMP were observed together with the periodic formation of cyclic AMP pulses, and the cyclic GMP peaks seemed to occur slightly in advance of the cyclic AMP peaks.
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