Trisomic dose of several chromosome 21 genes perturbs haematopoietic stem and progenitor cell differentiation in Down's syndrome

Children with Down's syndrome (DS) have 20–50-fold higher incidence of all leukaemias (lymphoid and myeloid), for reasons not understood. As incidence of many solid tumours is much lower in DS, we speculated that disturbed early haematopoietic differentiation could be the cause of increased leukaemia risk. If a common mechanism is behind the risk of both major leukaemia types, it would have to arise before the bifurcation to myeloid and lymphoid lineages. Using the transchromosomic system (mouse embryonic stem cells (ESCs)) bearing an extra human chromosome 21 (HSA21)) we analyzed the early stages of haematopoietic commitment (mesodermal colony formation) in vitro. We observed that trisomy 21 (T21) causes increased production of haemogenic endothelial cells, haematopoietic stem cell precursors and increased colony forming potential, with significantly increased immature progenitors. Transchromosomic colonies showed increased expression of Gata-2, c-Kit and Tie-2. A panel of partial T21 ESCs allowed us to assign these effects to HSA21 sub-regions, mapped by 3.5 kbp-resolution tiling arrays. The Gata-2 increase on one side, and c-Kit and Tie-2 increases on the other, could be attributed to two different, non-overlapping HSA21 regions. Using human-specific small interfering RNA silencing, we could demonstrate that an extra copy of RUNX1, but not ETS-2 or ERG, causes an increase in Tie-2/c-Kit levels. Finally, we detected significantly increased levels of RUNX1, C-KIT and PU.1 in human foetal livers with T21. We conclude that overdose of more than one HSA21 gene contributes to the disturbance of early haematopoiesis in DS, and that one of the contributors is RUNX1. As the observed T21-driven hyperproduction of multipotential immature precursors precedes the bifurcation to lymphoid and myeloid lineages, we speculate that this could create conditions of increased chance for acquisition of pre-leukaemogenic rearrangements/mutations in both lymphoid and myeloid lineages during foetal haematopoiesis, contributing to the increased risk of both leukaemia types in DS

Lack of evidence for association of meiotic nondisjunction with particular DNA haplotypes on chromosome 21.

The hypothesis of a predisposition to meiotic nondisjunction for chromosome 21 carrying a specific molecular haplotype has been tested. The haplotype in question is defined by the restriction fragment length polymorphisms for the D21S1/D21S11 loci. Our results obtained on a sample of Northern Italian families with the occurrence of trisomy 21 (Down syndrome) failed to support this hypothesis, contradicting a previous study [Antonarakis, S. E., Kittur, S. D., Metaxotou, C., Watkins, P. C. & Patel, A. S. (1985) Proc. Natl. Acad. Sci. USA 82, 3360-3364]. These findings rule out an association between any specific D21S1/D21S11 haplotype (as well as other haplotypes for the D21S13, ETS2, and D21S23 loci) and a putative cis-acting genetic element favoring the meiotic missegregation of chromosome 21. For this reason, no preventive screening for couples at risk for trisomy 21 may be based on any of the haplotypes tested

Familial infantile myoclonic epilepsy: Clinical features in a large kindred with autosomal recessive inheritance

Purpose: To describe the clinical features of a large kindred with familial infantile myoclonic epilepsy (FIME) with autosomal recessive inheritance, and to discuss the nosology of the early infantile myoclonic epilepsies (IMEs). Methods: The family descends from the intermarriage of two couples of siblings. In a previous study, we mapped the genetic locus to chromosome 16pl3.We analyzed results of family records and personal history, psychomotor development, neurologic examination, epilepsy features, and EEG recordings for each subject. Results: FIME has a strong penetrance (eight affected of 14 subjects) and a homogeneous clinical picture. Like the benign form of infantile myoclonic epilepsy (BIME), FIME is a true idiopathic IME with unremarkable history, no neurologic or mental impairment, good response to treatment, and normal interictal EEG pattern. Conversely, onset with generalized epileptic seizures without fever (four patients) or with fever (one patient), frequency and duration of the myoclonic seizures, occurrence of generalized tonic-clonic seizures (GTCSs) in all patients and persistence of seizures into adulthood are characteristics of the severe infantile myoclonic epilepsy (SIME). Conclusions: Clinical overlap probably exists among the myoclonic epilepsies of infancy. FIME differs from other forms of IME in its phenotypic features. The peculiar mode of inheritance is explained by the genetic background of the family. Genetic studies suggest linkage to chromosome 16 in familial cases of true IME

Increased levels of a chromosome 21-encoded tumour invasion and metastasis factor (TIAM1) mRNA in bone marrow of Down syndrome children during the acute phase of AML(M7)

Children with Down syndrome (DS) have a 10-20-fold increased risk of acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML), compared to non-DS children. The myeloid leukemia that accounts for nearly 50% of DS leukemias is usually the otherwise uncommon megakaryoblastic type (AML-M7). Though an etiological role of trisomy 21 in leukemogenesis has been suggested, the expression of genes on chromosome 21 in relation to trisomy, DS, and specific DS phenotypes such as leukemia is poorly understood. We used a heterologous-mimic competitive RT-PCR technique to measure the mRNA levels of a chromosome 21 tumour invasion and metastasis factor (TIAM1) directly in bone marrow samples of DS leukemic patients. In the limited number of cases analysed so far, we found TIAM1 mRNA levels in the DS AML-M7 samples of bone marrow taken in the acute phase of the disease (presentation or relapse, n=8) to be highly significantly raised, nearly threefold, compared to that measured in the remission samples or normal individuals (normals + remissions, n=10)

Mapping of a locus for a familial autosomal recessive idiopathic myoclonic epilepsy of infancy to chromosome 16p13.

Myoclonic epilepsies with onset in infancy and childhood are clinically and etiologically heterogeneous. Although genetic factors are thought to play an important role, to date very little is known about the etiology of these disorders. We ascertained a large Italian pedigree segregating a recessive idiopathic myoclonic epilepsy that starts in early infancy as myoclonic seizures, febrile convulsions, and tonic-clonic seizures. We typed 304 microsatellite markers spanning the 22 autosomes and mapped the locus on chromosome 16p13 by linkage analysis. A maximum LOD score of 4.48 was obtained for marker D16S3027 at recombination fraction 0. Haplotype analysis placed the critical region within a 3.4-cM interval between D16S3024 and D16S423. The present report constitutes the first example of an idiopathic epilepsy that is inherited as an autosomal recessive trait