Abnormal karyotypes occur in 0.3% of all newborn infants. Monosomy 1p36 is one of the most common chromosome abnormalities, occurring in 1/5,000 live births. In these patients, the size of the deletion varies from 1.5 to over 10.5 million base pairs (Mb). The characteristic clinical features include severe mental retardation, seizures, deafness, mild craniofacial anomalies and dilated cardiomyopathy. The molecular basis of this disorder is unknown. Our hypothesis is that haploinsufficiency of contiguous genes within the 1.5 Mb minimal region of deletion overlap is responsible for the etiology of 1p36 deletion syndrome (1p36DS). Since the deletions are >1.5 Mb (ARPM2-AGRN), it is not possible to identify the causative genes by human genetic approaches. Mouse models have been very helpful in elucidating the genetic basis for syndromes caused by hemizygous interstitial deletions. For this program, we propose to take an approach that is similar to what we have done in the past for velo-cardio-facial/DiGeorge syndrome on human chromosome 22q11.2.
In Specific Aim 1, we will identify candidate genes for the most notable features of 1p36DS. Considering that the anomalies are apparent at birth, it is likely that the defects will arise during embryogenesis. We will perform in situ hybridization studies of staged mouse embryos with gene-based probes prioritized according to their known function, expression pattern or structure. We will also examine relevant adult tissues. Because the majority of patients have most of the features of this syndrome, the causative genes likely reside in the most distal 1.5 Mb segment of 1p36. We will therefore generate a hemizygous 1.5 Mb deletion, from Arpm2 to Agrn, on mouse chromosome 4, to recapitulate the human condition in Specific Aim 2. This approach involves targeting Arpm2 and Agrn with loxP sites and selectable markers. Upon transient transfection with Cre recombinase, the intervening region will be deleted. Identification of the genes for 1p36DS will allow for therapeutic strategies to be developed.
