Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.

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Although dehydroepiandrosterone sulphate has been recognized as one of the major secretory products of the human adrenal gland neither its biosynthetic pathway nor its site of formation within the cortex have been extensively studied. Ultramicrochemical techniques, which relate enzymic activity to well-defined groups of cells, have been used in the work now described to study the sulphation of dehydroepiandrosterone in the zones of the guinea-pig adrenal cortex. It has been shown that dehydroepiandrosterone sulphokinase activity resides only in the compact cell of the zona reticularis.

As part of a continuing study of adrenal steroids in relation to breast cancer, various experiments were performed in order to study relationships between androgen and corticosteroid biosynthesis. Chopped tumour tissue from a 'mixed cell' adrenal adenoma (7\ m=. \ 4g.) removed from a patient in Cardiff Royal Infirmary was incubated with [4-14C]pregnenolone and [ 7\ g=a\ -3H]17\g=a\-hydroxypregnenolone for periods of time ranging from 30 to 120 min. The results of this work suggest that 17\g=a\-hydroxyprogesterone may not be an obligatory intermediate in androgen or cortisol synthesis. Evidence from further experiments with 'normal' human adrenal tissue removed from breast cancer patients using previously established ultramicrochemical techniques indicates that dehydroepiandrosterone (DHA) sulphokinase enzyme system is confined to the zona reticularis of the gland. The conversion of [7\g=a\-3H]DHA sulphate, [7\g=a\-3H]androstenedione and [7\g=a\-3H]testosterone to oestrogens and their conjugates by adrenal homogenates was also investigated. Conversions were extremely low from all precursors.