CA8 Mutations Cause a Novel Syndrome Characterized by Ataxia and Mild Mental Retardation with Predisposition to Quadrupedal Gait

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans

Acute myeloid leukemia: negative prognostic impact of early blast persistence can be in part overcome by a later remission prior to post-induction therapy

In acute myeloid leukemia, there is an ongoing debate on the prognostic value of the early bone marrow assessment in patients receiving intensive therapy. In this retrospective study, we analyzed the prognostic impact of the early response in 1,008 patients with newly diagnosed acute myeloid leukemia, who were treated at our institution with intensive chemotherapy followed by consolidation chemotherapy and/or allogeneic hematopoietic stem cell transplantation (HSCT). We found that early blast persistence has an independent negative prognostic impact on overall survival, eventfree survival and relapse-free survival. This negative prognostic impact may only be overcome in patients showing at least a partial remission at the early bone marrow assessment and who subsequently achieve blast clearance by additional induction chemotherapy prior to consolidation therapy with allogeneic HSCT. In accordance, we propose that the time slope of remission is an additional leukemia-related dynamic parameter that reflects chemosensitivity and thus may inform post-induction therapy decision-making. In addition to patient-related factors, European LeukemiaNet risk group, measurable residual disease monitoring and donor availability, this may particularly apply to European LeukemiaNet intermediate-risk patients, for whom a decision between consolidation chemotherapy and allogeneic HSCT remains challenging in many cases

Genome sequencing in families with congenital limb malformations

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified

Molecular analysis of monogenic inherited syndromes

Titelblatt und Inhaltsverzeichnis Zusammenfassung Einleitung Methodik Ergebnisse Ausblick und Schlußbemerkungen Literaturverzeichnis Danksagung ErklärungDie Molekulare Medizin verbindet die Bereiche Genetik, Biochemie und Medizin und hat in den letzten 10 Jahren unter Verwendung moderner genetischer und biochemischer Methoden zu einem rasanten Anstieg neuer Erkenntnisse geführt. Vor allem die erfolgreiche Entschlüsselung des menschlichen Genoms und die raschen Fortschritte in der Kartierung von Genen hat in vielen medizinischen Bereichen zu einem besseren Verständnis von Krankheitsursachen und zu neuen, wirksameren Therapiestrategien geführt. In immer stärkerem Maße werden die neuen diagnostischen und therapeutischen Möglichkeiten auf klinische Fragestellungen in der Humanmedizin angewandt und gewinnen auch im klinischen Alltag zunehmend an Bedeutung. Meine Arbeit beinhaltet molekulargenetische Untersuchungen für drei monogen bedingte Syndrome, Cerebellum-Hypoplasie und quadrupedaler Gang-Syndrom, Acromesomele Chondrodysplasie mit Genital- Anomalien und Sotos-Syndrom.Molecular medicine connects the divisions of genetics, biochemistry and medicine. Application of the more modern genetic and biochemical methods in the last ten years gave a rapid increase of new knowledge. Above all, the successful decoding of the human genome and the rapid progress in the mapping of genes has led in many medical areas to a better understanding of illness causes and to new, more effective therapy strategies. These new diagnostic and therapeutic possibilities are extensively applied to resolve clinical questions in the human medicine and also gain great importance in the clinical everyday life. My work contains the molecular genetic analysis of three monogenic inherited syndromes, Cerebellum hypoplasia and quadrupedal locomotion Syndrome, Acromesomelic chondrodysplasia with genital anomalies and Sotos syndrome

Genes and quadrupedal locomotion in humans

Ozcelik et al. (1) argue that mutations in VLDLR “cause quadrupedal locomotion in humans.” We have studied two of the families described in their paper, family A (2) and family B (3, 4). We have also investigated a family in Iraq in which four adult siblings habitually walk on all fours (ref. 5 and unpublished observations). If, as suggested, the condition is caused by a mutation that “leads to abnormal formation of the structures that are critical for gait,” we would expect quadrupedalism to occur when—but only when—this specific mutation is present. However, it turns out that the Iraqi family and three of the four Turkish families each carry a different mutation. Moreover, in Turkish family B, one individual with the same homozygous mutation as his affected siblings is not quadrupedal; and, in Hutterite families in North America, none of those with the same homozygous mutation as the affected individuals in families A and D are quadrupedal. In light of this, our conclusions are different from those of Ozcelik et al. We see quadrupedal locomotion as an adaptive—and undoubtedly effective—compensation for problems with balance caused by congenital cerebellar hypoplasia. We believe that the fact that this gait has not been “corrected” in the families under study must be attributed to the local cultural environment. As was proved with family B, during the making of a TV documentary, the provision of a walker could indeed make all the difference (see ref. 6)

Immunocytoexpression profile of ProExC in smears interpreted as ASC-US, ASC-H, and cervical intraepithelial lesion

WOS: 000393891700007PubMed ID: 28182079Aims: We aimed to investigate the immunocytoexpression profiles of a novel assay ProEx C for topoisomerase II alpha (TOP2A) and minichromosome maintenance protein 2 (MCM2) in abnormal interpreted smears. Settings and Design: Screening programs with Papanicolaou smear and high risk group human papilloma virus testing have yielded a dramatic reduction of cervical cancer incidence. However, both of these tests have limited specificity for the detection of clinically significant cervical high grade lesions. ProEx C for topoisomerase II alpha (TOP2A) and minichromosome maintenance protein 2 (MCM2) has been considered to have tight association with high grade intraepithelial lesions. Materials and Methods: A total number of 54 SurePath cervical cytology specimens of patients previously interpreted as atypical squamous cells-undetermined significance (ASC-US), atypical squamous cells-cannot exclude high grade squamous intraepithelial lesion (ASC-H), low grade squamous intraepithelial lesion (LSIL), and high grade squamous intraepithelial lesion (HSIL) were included in our study. Results and Conclusions: ProEx C was positive in 14 of HSILs (100%), 3 of 19 LSILs (16%), 2 of 4 ASC-Hs, and none of ASC-USs (0%). The ProEx C test showed very intense nuclear staining in all cytologically abnormal cells. Further studies are indicated to evaluate the diagnostic role of ProEx C

Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1

Brachydactyly type C (BDC) is characterized by shortening of the middle phalanges of the index, middle, and little finger with hyperphalangy, usually of the index and middle finger. Heterozygous mutations of the cartilage derived morphogenetic protein-1 (CDMP1) resulting in a loss of function have been reported in BDC. We here describe a large kindred with a semi-dominant form of BDC and pronounced ulnar deviation of the second and third digits. In this family a novel homozygous missense mutation was identified (517A > G) changing methionine to valine at amino acid position 173. The mutation is located within a highly conserved seven amino acid region of the prodomain of CDMP1. Hand radiographs of heterozygous mutation carriers showed mild shortening of the metacarpals IV and V; a finding confirmed by the analysis of their metacarpophalangeal profiles (MCPPs). The mutation described here points toward an important function of the prodomain for the folding, secretion, and availability of biologically active CDMP1

Original Articles Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia

Background Additional chromosomal aberrations in Philadelphia chromosome-positive chronic myeloid leukemia are non-random and strongly associated with disease progression, but their prognostic impact and effect on treatment response is not clear. Point mutations in the BCR-ABL kinase domain are probably the most common mechanisms of imatinib resistance. Design and Methods We assessed the influence of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to the second-generation tyrosine kinase inhibitor nilotinib after imatinib-failure. Standard cytogenetic analysis of metaphases was performed to detect additional chromosomal aberrations and the BCR-ABL kinase domain was sequenced to detect point mutations. Results Among 53 patients with a median follow-up of 16 months, of whom 38, 5 and 10 were in chronic phase, accelerated phase and blast crisis, respectively, 19 (36%) had additional chromosomal aberrations and 20 (38%) had BCR-ABL kinase domain mutations. The 2-year overall survival rate of all patients without additional chromosomal aberrations (89%) was higher than that of patients with such aberrations (54%) (P=0.0025). Among patients with chronic phase disease, overall survival at 2 years was 100% and 62% for patients without or with additional chromosomal aberrations, respectively (P=0.0024). BCR-ABL kinase domain mutations were associated with lower remission rates in response to nilotinib, with 9 of 20 (45%) of these patients achieving a major cytogenetic remission as compared to 26 of 33 (79%) patients without mutations (P<0.05). However, overall survival was not affected by BCR-ABL kinase domain mutations. Conclusions Whereas BCR-ABL kinase domain mutations may confer more specific resistance to nilotinib, which will predominantly affect response rates, the presence of additional chromosomal aberrations may reflect genetic instability and, therefore, intrinsic aggressiveness of the disease which will be less amenable to subsequent alternative treatments and thus negatively affect overall survival. Conventional cytogenetic analyses remain mandatory during follow-up of patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy. Key words: chronic myeloid leukemia, nilotinib, additionl chromosomal aberrations. Citation: Kim TD, Türkmen S, Schwarz M, Koca G, Nogai H, Bommer C, Dörken B, Daniel P, and le Coutre P. Impact of additional chromosomal aberrations and BCR-ABL kinase domain mutations on the response to nilotinib in Philadelphia chromosome-positive chronic myeloid leukemia. Haematologica. 2010;95:582-588. doi:10.3324/haematol.2009 This is an open-access paper. © F e r r a t a S t o r t i F o u n d a t i o n Impact of additional chromosomal aberrations and BCR-AB