Mutation prevalence of cerebral cavernous malformation genes in Spanish patients.

OBJECTIVE: To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co-occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations.

Germline fumarate hydratase mutations and evidence for a founder mutation underlying multiple cutaneous and uterine leiomyomata.

Multiple cutaneous and uterine leiomyomata syndrome (MCL) is an autosomal dominant disease characterized by the presence of concurrent benign tumors of smooth muscle origin (leiomyoma) in the skin and uterus of affected females, and in the skin of affected males. MCL can also be associated with type II papillary renal cell cancer (HLRCC). The genetic locus for MCL and HLRCC was recently mapped to chromosome 1q42.3-43 and subsequently, dominantly inherited mutations in the fumarate hydratase gene ( FH ) were identified. Importantly, analysis of the FH gene in tumors of MCL patients revealed a second mutation inactivating the wild-type allele in some tumors. Based on these findings, it has been suggested that FH may function as a tumor suppressor gene in MCL. Here, we report the analysis of the FH gene in a group of 11 MCL families, with the identification of 8 different mutations accounting for the disease in all families. One of the mutations, 905-1G>A, has been identified in 4 families of Iranian origin. The analysis of highly polymorphic markers in the vicinity of the FH gene showed a shared haplotype in these 4 families, suggesting that 905-1G>A represents a founder mutation. Collectively, identification of 5 novel and 3 recurrent mutations further supports the role of FH in the pathogenesis of MCL.

Identification of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy.

We have identified C7orf11, which localizes to the nucleus and is expressed in fetal hair follicles, as the first disease gene for nonphotosensitive trichothiodystrophy (TTD). C7orf11 maps to chromosome 7p14, and the disease locus has been designated "TTDN1" (TTD nonphotosensitive 1). Mutations were found in patients with Amish brittle-hair syndrome and in other nonphotosensititive TTD cases with mental retardation and decreased fertility but not in patients with Sabinas syndrome or Pollitt syndrome. Therefore, genetic heterogeneity in nonphotosensitive TTD is a feature similar to that observed in photosensitive TTD, which is caused by mutations in transcription factor II H (TFIIH) subunit genes. Comparative immunofluorescence analysis, however, suggests that C7orf11 does not influence TFIIH directly. Given the absence of cutaneous photosensitivity in the patients with C7orf11 mutations, together with the protein's nuclear localization, C7orf11 may be involved in transcription but not DNA repair.

Germline fumarate hydratase mutations in families with multiple cutaneous and uterine leiomyomata.

Germline mutations in the fumarate hydratase gene (FH) predispose to multiple cutaneous and uterine leiomyoma syndrome (MCL) and MCL associated with renal cell cancer. MCL is inherited in an autosomal dominant pattern, manifesting as skin leiomyoma and uterine fibroids in affected individuals. Fumarate hydratase, a component of the tricarboxylic acid cycle, acts as a tumor suppressor gene in the development of cutaneous and uterine leiomyoma and renal cell cancer in this syndrome. Here we report the clinical and mutational analysis of five families with MCL, with the identification of five new mutations affecting highly conserved residues of the FH protein. These results provide further evidence for the role of the FH gene in the pathogenesis of MCL.

A nonsense mutation in the desmoglein 1 gene underlies striate keratoderma.

Striate keratodermas (PPKS) (OMIM 148700) are a rare group of autosomal dominant genodermatoses characterized by palmoplantar keratoderma typified by streaking hyperkeratosis along each finger and extending onto the palm of the hand. We report a four-generation kindred originating from Iran-Syria in which three members were affected with PPKS. Clinically, these patients present with hyperkeratotic palms and plantar plaques. Direct DNA sequencing analysis revealed a heterozygous C-to-A transversion at nt 395 of the DSG1 gene. This mutation converted a serine residue (TCA) in exon 5 to a nonsense mutation (TAA) designated S132X. The mutation identified in this study is a novel mutation in the DSG1 gene and extends the body of evidence implicating the desmoglein gene family in the pathogenesis of human skin disorders.

A recurrent mutation in the ARS (component B) gene encoding SLURP-1 in Turkish families with mal de Meleda: evidence of a founder effect.

Mal de Meleda is a rare form of palmoplantar keratoderma, and recently mutations in the ARS (component) B gene have been identified in families with this disease. We identified a recurrent nonsense mutation, R96X, in four families of Turkish descent. In this report, we demonstrate that these families share a common ancestral haplotype at the mal de Meleda locus, suggesting a founder effect.

Evidence for pseudodominant inheritance of atrichia with papular lesions.

Atrichia with papular lesions is a rare form of total alopecia, in which mutations in the hairless gene have been shown to underlie the phenotype. In the literature to date, atrichia with papular lesions has generally been reported to be inherited in an autosomal recessive manner. A few rare cases exist, however, in which parent-to-child transmission of atrichia with papular lesions has been documented. In this study, further investigations were carried out into the molecular basis of atrichia with papular lesions in a family with mother-to-son transmission by searching for mutations in the human hairless gene. Specific ally, we wanted to determine whether this case truly represented an example of dominantly inherited atrichia with papular lesions, or whether another mode of inheritance might be responsible for the disorder in this kindred. Pseudodominant inheritance, for example, occurs when an individual with a known recessive disorder has a clinically unaffected partner, but then unexpectedly gives birth to children who are affected with the same recessive disorder as the affected parent, and can easily be distinguished from classical dominant inheritance with molecular diagnosis and haplotype analysis. In the family reported here, we have determined that both the mother and son are, in fact, homozygous for a novel mutation in the hairless gene, R33X. We provide the first evidence for pseudodominant inheritance in atrichia with papular lesions, and at the same time extend our knowledge of pathogenetic mutations in the human hairless gene. Importantly, this information allows revisions in genetic counseling for risk of transmission for individuals in the family, previously impossible in the absence of knowing the genetic basis of atrichia with papular lesions in this unusual kindred.

Multiple cutaneous and uterine leiomyomas: refinement of the genetic locus for multiple cutaneous and uterine leiomyomas on chromosome 1q42.3-43.

Cutaneous leiomyomas, rare benign tumors originating from the arrector pili muscle of the hair follicle, can be associated with the common uterine fibroids in a syndrome called multiple cutaneous and uterine leiomyomas. Multiple cutaneous and uterine leiomyomas are inherited as an autosomal dominant trait, providing an excellent opportunity for the study of the common non-Mendelian manifestation of isolated uterine fibroids. This study reports the clinical and molecular characterization of an extended family with multiple cutaneous and uterine leiomyomas. Linkage analysis has shown that the disease in this family is linked to the recently reported genetic locus for multiple cutaneous and uterine leiomyomas, with a maximum two-point LOD score of 4.453 for markers D1S2670, D1S2785, D1S547, and D1S1609. The identification of key recombination events has allowed us to refine substantially the location of the genetic locus for multiple cutaneous and uterine leiomyomas, from 14 cM to an interval of 4.55 or 7.19 cM, depending on the final phenotype of a young family member in which one of the key recombination events has occurred. In addition, we provide a description of the interesting pattern and progression of the skin phenotype in this four-generation kindred. The refinement of the genetic locus for multiple cutaneous and uterine leiomyomas and the availability of an extended multigeneration pedigree will facilitate the identification of the mutated gene responsible for multiple cutaneous and uterine leiomyomas, which, in turn, may provide key information for the understanding of the molecular basis of the common uterine fibroids.