LSD1/KDM1A is essential for neural stem cell differentiation in mice.

The proper regulation of neural stem cell differentiation is required for the proper specification of the central nervous system. Here we investigated the function of the H3K4me1/2 demethylase LSD1/KDM1A during neural stem differentiation in mice. Conditional deletion of LSD1 in nestin- positive neural stem cells results in 100% perinatal lethality after birth with severe motor coordination deficits, retarded growth and defects in brain morphology. Despite these severe defects, motor neuron progenitors and the initial motor neuron population are specified normally and motor neurons with normal morphology can be cultured from these mice in vitro. However, motor neurons cultured from mice lacking LSD1 in neural stem cells continue to inappropriately maintain critical neural stem cell proteins. Taken together these results suggest that, as in other mouse stem cell populations, LSD1 is required to deactivate the stem cell program to enable normal neural stem cell differentiation. However, unlike in other mouse stem cell populations, the inappropriate maintenance of the stem cell program during neural stem cell differentiation may compromise neuronal function rather than neuronal specification.

Monoallelic expression of mutant thyroid peroxidase allele causing total iodide organification defect.

Mutations in the thyroid peroxidase (TPO) gene lead to severe congenital hypothyroidism due to total iodide organification defect (TIOD). According to the recessive mode of inheritance, patients are homozygous or compound heterozygous for gene mutations. However, about 17% of cases with typical phenotype harbor a single TPO-mutated allele. We present a TIOD family in which the three affected siblings had a single genomic TPO mutation (R693W) inherited from the unaffected father. Other mutations were not found, although all TPO coding exons and exon/intron boundaries were sequenced. Eleven different polymorphisms were found in hetero- or homozygosity in all family members. On the contrary, using retrotranscribed thyroid tissue RNA, all heterozygous polymorphisms and the mutation were homozygous. The distribution of the polymorphisms indicated that only the mutant paternal allele is transcribed at the thyroid tissue level. We excluded the presence of major deletions involving the maternal chromosome at 2p25 and of maternal imprinting or mutations in part of the regulatory regions of the gene. In summary, we report one family with TIOD due to monoallelic expression of a mutant TPO allele in the thyroid. This mechanism might be generally involved in TIOD cases with a single TPO-mutated allele.