Molecular and clinical studies in 8 patients with Temple syndrome.

Temple syndrome (TS14, #616222) is a rare imprinting disorder characterised by phenotypic features including pre- and postnatal growth retardation, muscular hypotonia and feeding difficulties in infancy, early puberty and short stature with small hands and feet and often truncal obesity. It is caused by maternal uniparental disomies, paternal deletions and primary imprinting defects that affect the chromosomal region 14q32 and lead to a disturbed expression of imprinted genes in this region. Here, we present detailed clinical data of 8 patients with Temple syndrome, 4 with an imprinting defect, 2 with an imprinting defect in a mosaic state as well as 1 complete and 1 segmental maternal uniparental disomy of chromosome 14.

Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.

BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown. METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry. RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4. CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

MOTA Syndrome: Molecular Genetic Confirmation of the Diagnosis in a Newborn with Previously Unreported Clinical Features.

MOTA syndrome, the acronym for Manitoba-oculo-tricho-anal syndrome (OMIM 248450), is a distinct autosomal recessive multiple malformation syndrome caused by mutations in the FREM1 gene (OMIM 608944). Eight patients with MOTA syndrome and a pathogenic FREM1 mutation have previously been documented. We report on a new male patient, 3.5 months old, with MOTA syndrome, who presented with the following features: bilateral incomplete cryptophthalmos with a completely fused, ill-defined upper eyelid and a keratinized cornea, hypertelorism, a broad tip of the nose, a circle-shaped whirl of hair on the forehead, and a low anorectal malformation, which could be corrected on day 2 of life without a colostomy. In expansion to the previously reported phenotype of MOTA syndrome, the patient showed characteristic features reported in patients with Fraser syndrome, including dysplastic ears, cutaneous syndactyly 3/4 of the hands and syndactyly 2/3 of the right foot. Molecular analysis of FREM1 identified compound heterozygosity for a new frameshift deletion in exon 24 (c.4629delC, p.F1544SfsX62) and a previously reported missense mutation in exon 21 (c.3971T>G, p.L1324R). This report further extends the phenotype of MOTA syndrome and underscores the overlapping clinical spectrum of FRAS-FREM complex diseases.

Two Missense Mutations in the Primary Autosomal Recessive Microcephaly Gene MCPH1 Disrupt the Function of the Highly Conserved N-Terminal BRCT Domain of Microcephalin.

Primary microcephaly MCPH1 is an extremely rare autosomal recessive disorder associated with congenital microcephaly, mental retardation and a distinctive cellular phenotype of misregulated chromosome condensation. The MCPH1 gene encodes an 835-amino acid protein, microcephalin, which contains 1 N-terminal and 2 C-terminal BRCT (BRCA1 C-terminus) domains. BRCT domains are predominantly found in proteins involved in cell cycle control and DNA repair. Here we describe 1 novel and 1 previously reported MCPH1 missense mutation, p.Trp75Arg and p.Ser72Leu, respectively, in the N-terminal BRCT domain of microcephalin associated with severe congenital microcephaly. Both residues are entirely conserved in the MCPH1 orthologs of all vertebrate species and Drosophila. Proliferating lymphocytes of the patients with p.Trp75Arg and p.Ser72Leu show the unique cellular MCPH1 phenotype of misregulated chromosome condensation, indicating that these missense alterations disrupt the function of the N-terminal BRCT domain of the protein. Interestingly, both residues are strictly conserved in BRCT domains of BRCA1. ClustalW alignments show that the residue p.Ser72 of microcephalin corresponds to p.Ser1715 of the N-terminal BRCT domain of BRCA1, while the microcephalin residue p.Trp75 is analogous to p.Trp1718 in the N-terminal BRCT and to p.Trp1837 in C-terminal BRCT domains of BRCA1. Missense alterations for all 3 corresponding BRCA1 residues were described and are predicted to be deleterious resulting in the destabilization of the BRCA1 protein. Our data on the 2 MCPH1 missense alterations provide further evidence for the functional significance of these residues in BRCT domains.

[Estrogen receptor Beta isoforms -- functions and clinical relevance in breast cancer]. / Ostrogenrezeptor-beta-Isoformen--Funktionen und klinische Bedeutung bei Brustkrebs.

Estrogen receptors (ER) are hormone regulated transcription factors which mediate the cellular estrogen response. So far two types of ER could be identified, ERalpha and ERbeta. ERalpha plays an important role as a predictive factor for the effectiveness of endocrine agents in the treatment of breast cancer. Patients with ERalpha positive tumors receive adjuvant endocrine therapy. Recent findings indicate a crucial role of ERbeta and its isoforms for the prognosis of breast cancer. This paper reviews the current knowledge on the functions of ERbeta and its splice variants.

Activity-dependent changes of the presynaptic synaptophysin-synaptobrevin complex in adult rat brain.

The vesicular protein synaptobrevin contributes to two mutually exclusive complexes in mature synapses. Synaptobrevin tightly interacts with the plasma membrane proteins syntaxin and SNAP 25 forming the SNARE complex as a prerequisite for exocytotic membrane fusion. Alternatively, synaptobrevin binds to the vesicular protein synaptophysin. It is unclear whether SNARE complex formation is diminished or facilitated when synaptobrevin is bound to synaptophysin. Here we show that the synaptophysin-synaptobrevin complex is increased in adult rat brain after repeated synaptic hyperactivity in the kindling model of epilepsy. Two days after the last kindling-induced stage V seizure the relative amount of synaptophysin-synaptobrevin complex obtained by co-immunoprecipitation from cortical and hippocampal membranes was increased twofold compared to controls. By contrast the relative amounts of various synaptic proteins as well as that of the SNARE complex did not change in membrane preparations from kindled rats compared to controls. The increased amount of synaptophysin-synaptobrevin complex in kindled rats supports the idea that this complex represents a reserve pool for synaptobrevin enabling synaptic vesicles to adjust to an increased demand for synaptic efficiency. We conclude that the synaptophysin-synaptobrevin interaction is involved in activity-dependent plastic changes in adult rat brain.