LAUSR

The first case of a rare autosomal dominant disorder charac - terized by short - limbed short stature [and the subject of the studies in Höppner et al. ( 1 )] was reported by Jansen ( 2 ). The disorder now recognized as Jansen’s metaphyseal chondro - dysplasia (JMC; OMIM# 156400) is the result of delayed chon - drocyte differentiation and characterized by short - limbed dwarfism, bowed legs, waddling gait, and typically severe hypercalcemia and hypophosphatemia, despite normal or low levels of parathyroid hormone (PTH). JMC is diagnosed during childhood (less than 10 y of age), based on a combination of radiographic and biochemical abnormalities, however, some patients with less severe dis - ease may not be diagnosed until some years later in adult - hood. Most JMC cases arise from de novo mutations in the disease - causing PTH/PTHrP receptor (PTH1R) gene ( 3 ) and for which there are currently no available treatment options. To date, five different heterozygous activating PTH1R muta - tions that change one of three different amino acid residues in PTH1R (His223, Thr410, or Ile458) ( 4 ) are known to cause JMC, with most affected patients presenting with the H223R mutation ( 5 ). With this knowledge in hand and building on earlier work from the group that had identified activating mutations in the PTH1R gene as the molecular culprit in JMC ( 4 ), Höppner et al. embarked on an elegant series of exper - iments that have resulted in the development of a human - ized mouse model of JMC. What is a humanized mouse model and why generate one?