Many p53 missense mutations possess dominant-negative activity and oncogenic gain of function. We report that for structurally destabilized p53 mutants, these effects result from mutant-induced coaggregation of wild-type p53 and its paralogs p63 and p73, thereby also inducing a heat-shock response. Aggregation of mutant p53 resulted from self-assembly of a conserved aggregation-nucleating sequence within the hydrophobic core of the DNA-binding domain, which becomes exposed after mutation. Suppressing the aggregation propensity of this sequence by mutagenesis abrogated gain of function and restored activity of wild-type p53 and its paralogs. In the p53 germline mutation database, tumors carrying aggregation-prone p53 mutations have a significantly lower frequency of wild-type allele loss as compared to tumors harboring nonaggregating mutations, suggesting a difference in clonal selection of aggregating mutants. Overall, our study reveals a novel disease mechanism for mutant p53 gain of function and suggests that, at least in some respects, cancer could be considered an aggregation-associated disease.

Partial monosomy 16 is a characteristic lesion in spindle cell lipoma, usually associated with anomalies of chromosome 13. The present report confirming a previous single observation indicates, however, that lesions of 13 may occur independently from lesions of 16, suggesting different underlying molecular lesions in these otherwise very similar lipomas.

We present autopsy studies in 4 unrelated fetuses with the lethal multiple pterygium syndrome (LMPS) with special emphasis on the neuromuscular system. The data suggest that LMPS combines the manifestations of a jugular lymphatic obstruction sequence with those of an early severe fetal akinesia sequence. The jugular lymphatic obstruction sequence with resultant edema and cystic hygroma colli causes fetal lethality usually in the second trimester of pregnancy. Generalized amyoplasia appears to be an important mechanism in the pathogenesis of fetal akinesia as part of LMPS and is not associated with dysgenesis or degeneration of the central nervous system (CNS) but is apparently the result of an early fetal muscular "dystrophy." We propose a genetically determined insult affecting the early embryonic development of both lymph vessels and muscles as the basic defect in LMPS. Placental structure, studied in all 4 cases, demonstrated that triploidy-like placental lesions are specific to LMPS. The present findings suggest that LMPS may be a less heterogeneous entity than previously proposed.

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In an autopsy study of 37 infants who suffered from hyaline membrane disease (HMD), two distinct patterns of pulmonary lesions could be defined. One pattern, characterized by marked interstitial fibrosis in the absence of airway abnormalities, was labelled Ê»interstitial-type’ histology. A second type, labelled Ê»bronchiolar-type’ histology, showed marked airway lesions and alveolar emphysema. Nine patients of each type were analysed. Nineteen other patients had a Ê»mixed-type’ histology and were not further studied. Retrospectively, the clinical and radiological characteristics of both series were analysed. No differences in birth weight, gestational age and initial radiological HMD grade could be demonstrated. The pulmonary function of the bronchiolar-type patients however was significantly worse at the onset, and these infants needed more oxygen and ventilatory support during the first 10 days of life. They all died from respiratory failure whereas 4 patients from the interstitial group had non-pulmonary fatalities. In the bronchiolar group chest X-rays showed atelectasis and pulmonary interstitial emphysema in the early stages, and hyperinflation with bullae and irregular streaky densities in the later. Patients in the interstitial group had no or minor emphysema with more homogeneously spread densities over both lungs. We conclude that both types of evolution represent two extremes of the bronchopulmonary dysplasia spectrum.