Luitgard Neumann

Mutations in Microcephalin Cause Aberrant Regulation of Chromosome Condensation

Microcephalin (MCPH1) is a gene mutated in primary microcephaly, an autosomal recessive neurodevelopmental disorder in which there is a marked reduction in brain size. PCC syndrome is a recently described disorder of microcephaly, short stature, and misregulated chromosome condensation. Here, we report the finding that MCPH1 primary microcephaly and PCC syndrome are allelic disorders, both having mutations in the MCPH1 gene. The two conditions share a common cellular phenotype of premature chromosome condensation in the early G2 phase of the cell cycle, which, therefore, appears to be a useful diagnostic marker for individuals with MCPH1 gene mutations. We demonstrate that an siRNA-mediated depletion of MCPH1 is sufficient to reproduce this phenotype and also show that MCPH1-deficient cells exhibit delayed decondensation postmitosis. These findings implicate microcephalin as a novel regulator of chromosome condensation and link the apparently disparate fields of neurogenesis and chromosome biology. Further characterization of MCPH1 is thus likely to lead to fundamental insights into both the regulation of chromosome condensation and neurodevelopment.

Partial deficiency of the C-terminal-domain phosphatase of RNA polymerase II is associated with congenital cataracts facial dysmorphism neuropathy syndrome

Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome (OMIM 604168) is an autosomal recessive developmental disorder that occurs in an endogamous group of Vlax Roma (Gypsies; refs. 1–3). We previously localized the gene associated with CCFDN to 18qter, where a conserved haplotype suggested a single founder mutation. In this study, we used recombination mapping to refine the gene position to a 155-kb critical interval. During haplotype analysis, we found that the non-transmitted chromosomes of some unaffected parents carried the conserved haplotype associated with the disease. Assuming such parents to be completely homozygous across the critical interval except with respect to the disease-causing mutation, we developed a new not quite identical by descent (NQIBD) approach, which allowed us to identify the mutation causing the disease by sequencing DNA from a single unaffected homozygous parent. We show that CCFDN is caused by a single-nucleotide substitution in an antisense Alu element in intron 6 of CTDP1 (encoding the protein phosphatase FCP1, an essential component of the eukaryotic transcription machinery), resulting in a rare mechanism of aberrant splicing and an Alu insertion in the processed mRNA. CCFDN thus joins the group of transcription syndromes and is the first purely transcriptional defect identified that affects polymerase II–mediated gene expression.

Premature Chromosome Condensation in Humans Associated with Microcephaly and Mental Retardation: A Novel Autosomal Recessive Condition

We report a novel autosomal recessive disorder characterized by premature chromosome condensation in the early G2 phase. It was observed in two siblings, from consanguineous parents, affected with microcephaly, growth retardation, and severe mental retardation. Chromosome analysis showed a high frequency of prophase-like cells (>10%) in lymphocytes, fibroblasts, and lymphoblast cell lines with an otherwise normal karyotype. (3)H-thymidine-pulse labeling and autoradiography showed that, 2 h after the pulse, 28%-35% of the prophases were labeled, compared with 9%-11% in healthy control subjects, indicating that the phenomenon is due to premature chromosome condensation. Flow cytometry studies demonstrate that the entire cell cycle is not prolonged, compared with that in healthy control subjects, and compartment sizes did not differ from those in healthy control subjects. No increased reaction of the cells to X-irradiation or treatments with the clastogens bleomycin and mitomycin C was observed, in contrast to results in the cell-cycle mutants ataxia telangiectasia and Fanconi anemia. The rates of sister chromatid exchanges and the mitotic nondisjunction rates were inconspicuous. Premature entry of cells into mitosis suggests that a gene involved in cell-cycle regulation is mutated in these siblings.

Toriello-Carey syndrome: Delineation and review

Toriello and Carey [1988: Am J Med Genet 31:17–23] first described a syndrome with component manifestations of corpus callosum agenesis, unusual facial appearance, Robin sequence, and other anomalies. This was termed the Toriello–Carey syndrome by Lacombe et al. [1992: Am J Med Genet 42:374–376]. Since then, 11 reports describing 16 additional children have been published; in addition, we have had the opportunity to review over 30 unpublished cases. However, for various reasons, only 25 of the unpublished patients were included in this review. Based on this total, we can begin to better delineate this syndrome, as well as provide some information on natural history.

Mild Ventriculomegaly, Mild Cerebellar Hypoplasia and Dysplastic Choroid Plexus as Early Prenatal Signs of CHARGE Association

CHARGE association has been diagnosed postnatally in increasing numbers since the first description in 1979. The acronym CHARGE includes the abnormalities ocular Colobomas (iris, retina or nervus opticus), Heart disease, Atresia of choanae, Retarded growth and development and/or central nervous system anomalies, Genital hypoplasia, Ear anomalies and deafness. So far, no prenatal diagnosis of the CHARGE association has been described; only one case report presents prenatal symptoms detected at 31 gestational weeks. In our case, prenatally detected mild cerebral ventriculomegaly and dysplasia of choroid plexus were abnormalities visible as early as 15+6 weeks as well as mild cerebellar hypoplasia at 21+1 weeks. At 28+6 weeks, in addition polyhydramnios could be found. The combination of the ‘benign’ central-nervous findings raised suspicion of a severe congenital malformation at 21+1 weeks which was confirmed postnatally in the form of diagnosis of CHARGE association.

Characterization of a supernumerary ring chromosome 1 mosaicism in two cell systems by molecular cytogenetic techniques and review of the literature

We report on a 4‐year‐old boy with developmental delay and microcephaly with an additional small marker chromosome derived from chromosome 1 and detected in 14% of T‐lymphocytes by conventional cytogenetics and in 9% of buccal smear cells by interphase FISH. Using molecular cytogenetic techniques, the marker chromosome was characterized as an extra ring chromosome consisting of euchromatic material from the proximal short arm of chromosome 1. We compare the cytogenetic data and the phenotype of our patient to those previously described cases with marker chromosome 1 mosaicism. We conclude that in addition to the straightforward molecular cytogenetic characterization of the euchromatic content of the ring chromosome, the investigation of a second cell system gives additional information about the tissue specific distribution of the supernumerary marker chromosome (SMC) and provides more reliable data for further karyotype/phenotype correlations and the prediction of the phenotypic outcome in prenatal cases.

Unilateral terminal aphalangia in father and daughter—exogenous or genetic cause?

Published cases of familial unilateral terminal transverse defects are scarce. We report on a morphologically similar defect of the hand in a father and his daughter. The hand anomaly is similar in both, but on the opposite side. Thalidomide was taken in the sensitive period of the pregnancy by the fathers mother. To our knowledge this is the second description of unilateral terminal aphalangia in successive generations. In order to evaluate the possible genetic basis we analyze epidemiological studies in respect to the recurrence risk of cases with isolated limb reduction defects. We compare reports of familial occurrence concerning the degree of relationship as well as the pattern of malformation. The latter seems to be an important aspect from an evolutionary and a developmental viewpoint. For our observation an autosomal dominant transmission is the most likely although multifactorial determination cannot be excluded.

Clinical and genetic screening in patients with capillary retinal angioma

SummaryCapillary retinal angiomas are rare vascular tumors that frequently occur in von Hippel-Lindau syndrome (vHL) but may also be sporadic. In all patients presenting with this tumor a thorough search for other vHL-associated lesions must be performed. After identification of the vHL gene on the short arm of chromosome 3 (3p25–26), the diagnosis is supported by molecular genetic analysis.nPatients: In 20 patients with retinal angioma a clinical search for other manifestations of vHL was performed. In 5 patients only one angioma was present. In all patients molecular genetic tests for a mutation of the vHL gene were performed by SSCP and direct sequencing.nResults: In 16 (80 %) patients vHL was present, and in 15 it could be diagnosed by clinical findings or a positive familiy history. Organ lesions in vHL patients were CNS hemangioblastoma in 10 (63 %), pancreatic cysts in 7 (43 %) and renal cysts in 7 (43 %) patients. In two patients (13 %) renal carcinoma could be detected; in one patient a pheochromcytoma was present. A mutation could be detected in all 15 patients with clinically confirmed vHL. In three patients a new mutation of vHL disease was diagnosed genetically. In one of these patients a single retinal angioma was the only sign of vHL.nConclusion: In patients presenting with capillary retinal angioma a careful search for other vHL lesions has to be performed. A mutation of the vHL gene can be detected in the majority of patients; thus, moleculargenetic testing is a powerful tool for diagnosis and detection of asymptomatic gene- carriers.ZusammenfassungHintergrund: Kapilläre retinale Angiome treten in der Regel im Rahmen eines von Hippel-Lindau-Syndroms (vHL), selten sporadisch auf. Bei allen Patienten mit einem solchen Tumor ist eine Untersuchung auf das Vorliegen weiterer Organmanifestationen eines vHL unerläßlich. Nachdem das auf dem kurzen Arm des Chromosoms 3 (3p25–26) lokalisierte vHL-Gen identifiziert wurde, kann die molekulargenetische Diagnostik die Diagnose bestätigen.nPatienten und Methode: Bei 20 Patienten mit retinalen Angiomen wurden klinische Untersuchungen für weitere Organmanifestationen eines vHL durchgeführt. Bei 5 dieser Patienten bestand ein solitäres Angiom. Bei allen Patienten wurde eine molekulargenetische Untersuchung auf das Vorliegen einer Mutation des vHL-Gens durchgeführt.nErgebnisse: Bei 16 (80 %) Patienten bestand ein vHL, welches bei 15 Patienten klinisch oder familienanamnestisch nachweisbar war. Bei 10 (63 %) dieser Patienten bestanden zentralnervöse Hämangioblastome. Pankreaszysten und Nierenzysten fanden sich bei jeweils 7 Patienten (44 %), bei 2 Patienten (13 %) wurde ein Nierenzellkarzinom gefunden. Bei einem Patienten bestand ein Phäochromozytom. Molekulargenetisch konnte bei allen 15 Patienten mit klinisch gesichertem vHL eine Mutation des vHL-Gens nachgewiesen werden. Bei 3 Patienten lag wahrscheinlich eine Neumutation vor, bei einem dieser Patienten bestand lediglich ein solitäres retinales Angiom als einziges Zeichen des Syndroms.nSchlußfolgerung: Bei Patienten mit kapillären retinalen Angiomen muß eine sorgfältige Suche nach weiteren Organmanifestationen eines von Hippel-Lindau-Syndroms erfolgen. Da eine Mutation des vHL-Gens bei den meisten erkrankten Patienten nachgewiesen werden kann, ist die molekulargenetische Diagnostik zur Sicherung der Diagnose und zur Untersuchung nicht erkrankter Verwandter auf Genträgerschaft geeignet.

A new observation of two cases of acrofacial dysostosis type Genée-Wiedemann in a family—remarks on the mode of inheritance: Report on two sibs†

We report on a Yugoslavian sibpair with postaxial acrofacial dysostosis type Genée-Wiedemann with some novel signs which broaden the spectrum of this syndrome. The manifestations of the present cases are compared with those of the previously described patients. Life expectancy, change of symptoms over time, and the mode of inheritance are discussed.