CADASIL with a novel mutation in exon 7 of NOTCH3 (C388Y).

We report a 38-year-old Japanese woman who had cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) with a novel mutation (TGT to TAT) at nucleotide position 1241 (C388Y) in exon 7 of the Notch3 gene (NOTCH3). Immunostaining of a skin biopsy with a Notch3 monoclonal antibody is a beneficial method for the screening of CADASIL, particularly in the case of rare mutations outside the mutation hotspots in NOTCH3 as shown in this patient.

Clinical features of cerebral cavernous malformations patients with KRIT1 mutations.

Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being characterized by the presence of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers. Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom-free. Mean age at clinical onset was 29.7 years (range, 2-72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (+/-7.2) and on gradient echo sequences 19.8 (+/-33.2). Twenty-six mutation carriers harbored only one lesion on T2-weighted MRI, including 4 mutation carriers, aged from 18 to 55 yr-old, who presented only one CCM lesion both on T2-weighted and on highly sensitive gradient echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr-old, did not have any detectable lesion both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation carriers aged 50 or more are symptom-free. The presence of only one lesion, even when using gradient echo MRI sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be overlooked in some mutation carriers presenting as sporadic cases with a unique lesion.

JAML, a novel protein with characteristics of a junctional adhesion molecule, is induced during differentiation of myeloid leukemia cells.

Retinoic acid induces clinical remission in acute promyelocytic leukemia (APL) by triggering differentiation of leukemia promyelocytes. Here, we have characterized a gene encoding a member of the immunoglobulin superfamily, among novel retinoic acid-induced genes identified in APL cells. This protein, which was named JAML (junctional adhesion molecule-like), contains 2 extracellular immunoglobulin-like domains, a transmembrane segment, and a cytoplasmic tail. JAML mRNA is expressed in hematopoietic tissues and is prominently expressed in granulocytes. The fact that JAML protein is localized at the cell plasma membrane in the areas of cell-cell contacts, whereas it is not detected at free cell borders, suggests that JAML is engaged in homophilic interactions. Furthermore, a conserved dimerization motif among JAM members was shown to be important for JAML localization at the cell membrane. Finally, exogenous expression of JAML in myeloid leukemia cells resulted in enhanced cell adhesion to endothelial cells. Altogether, our results point to JAML as a novel member of the JAM family expressed on leukocytes with a possible role in leukocyte transmigration.

Spectrum and expression analysis of KRIT1 mutations in 121 consecutive and unrelated patients with Cerebral Cavernous Malformations.

Cerebral Cavernous Malformations (CCM/MIM 604214) are vascular malformations characterised by abnormally enlarged capillary cavities without intervening brain parenchyma. Clinical manifestations include seizures, cerebral haemorrhages and focal neurological deficits. They occur as a sporadic or autosomal dominant condition. Most often, sporadic cases have only one lesion and familial cases are characterised by a high frequency of multiple lesions. Three CCM loci were previously mapped on 7q (CCM1), 7p (CCM2) and 3q (CCM3) and CCM1 gene was identified as coding Krit1, a protein of unknown function, which was shown initially to interact in yeast two hybrid assays with Rap1A, a small ras GTPase and more recently to Icap1alpha, a modulator of beta1 integrin signal transduction. Herein, we screened KRIT1 gene in 121 unrelated, consecutively recruited, CCM probands having at least one affected relative and/or showing multiple lesions on cerebral MRI. Fifty-two of these probands (43%) were shown to carry a KRIT1 mutation. Forty-two distinct mutations were identified including six recurrent ones. Three-quarters of these mutations were located in the C-terminal half of the gene, mostly within exons 13, 15 and 17. All of them are predicted to lead to a premature stop codon. No missense mutation was identified. The only two nucleotide substitutions predicted to be missense mutations led in fact to an abnormal splicing and a premature stop codon. Altogether these data suggest that KRIT1 mRNA decay due to the presence of premature stop codons and Krit1 haploinsufficiency may be the underlying mechanism of CCM.

Association of genetic defects in primary resected lung adenocarcinoma revealed by targeted allelic imbalance analysis.

Genetic mechanisms underlying origin and progression of lung cancer are still poorly understood, despite the numerous studies which identified many genomic alterations. Using polymorphic microsatellites, allelic imbalances have been frequently found at loci such as 3p, 5q, 8p, 9p and 9q, 11p and 11q, and 17q without either histologic specificity or prognosis value. We report allelotyping results in 54 cases (50 smokers) of primary lung adenocarcinoma (50 men/4 women) resected at one institution. To perform this study, a panel of seven microsatellites were chosen upon their likely involvement in lung cancer or in the cell cycle. A highly sensitive method was designed using fluorescent PCR coupled with quantification on an automated DNA sequencer. We report that at least one allelic imbalance was observed in 87% of adenocarcinoma. Alterations at 17q23 tended to be associated with early stage tumors (I and II) and longer survivals (P = 0.05 and P = 0.06, respectively). Furthermore, concomitant alterations were found at 9p21 and at either 9q34 or 3p24 loci (P = 0.003 and P = 0.004, respectively). The presence of genes coding for TGF-beta receptors I and II at these loci suggests that the TGF-beta/CDK inhibitor P16/P15 signaling pathway might be involved in lung adenocarcinoma development.