Monosomy 21 is a rare human disease due to gene dosage errors disturbing a variety of physiological and morphological systems including brain, skeletal, immune and respiratory functions. Most of the human condition corresponds to partial or mosaic monosomy suggesting that Monosomy 21 may be lethal. In order to search for dosage-sensitive genes involved in the human pathology, we generated by chromosomal engineering a monosomic mouse for the Prmt2–Col6a1 interval corresponding to the most telomeric part of human chromosome 21. Haploinsufficiency of the 13 genes, located in the 0.5 Mb genetic interval and conserved in man and mouse, caused apparently no morphological defect as observed in patients. However, monosomic mice displayed an enhanced inflammatory response after local intranasal lipopolysaccharide administration with enhanced recruitment of neutrophils and secretion of cytokines such as tumor necrosis factor-α (TNF-α), IL-1β, IL-12p70 and IFN-γ in the lung as well increased TNF-α production after systemic administration. Further analysis demonstrates that monosomic macrophages were involved and that a few genes, Prmt2 , Pcnt2 , Mcm3ap and Lss located in the region were candidate for the inflammatory response. Altogether, these results demonstrate the existence of dosage-sensitive genes in the Prmt2–Col6a1 region that control the inflammation and the lung function. Furthermore, they point out that similar partial Monosomies 21 in human might have eluded the diagnosis due to the very specific defects observed in this murine model.