SummaryA screen of activation-tagged Arabidopsis lines resulted in the identification of At1g01380, which encodes a small R3 single repeat MYB gene, as a negative regulator of trichome initiation. Plants that overexpress this gene have fewer trichomes. The gene is closely related to the previously identified negative regulator TRY, and has a similar pattern of expression as TRY in developing leaves. As previously shown for TRY, At1g01380 protein can inhibit the interaction between the positive trichome regulators GL1 and GL3, and likely limits trichome initiation via this inhibition. While TRY and At1g01380 are closely related, they are not completely functionally equivalent. When placed under the transcriptional control of the TRY promoter, At1g01380 can only partially rescue the try mutant. Interestingly, Atg01380 is highly expressed in gl3-sst trichomes, while TRY expression is greatly reduced. The mutation in gl3-sst causes a reduced interaction between the GL1 and GL3 proteins and results in fewer leaf trichomes that develop in clusters. The differential expression of TRY and At1g01380 in this mutant can be used to explain how its altered trichome pattern in gl2-sst is generated.

BackgroundElevated urinary excretion of orotic acid is associated with treatable disorders of the urea cycle and pyrimidine metabolism. Establishing the correct and timely diagnosis in a patient with orotic aciduria is key to effective treatment. Uridine monophosphate synthase is involved in de novo pyrimidine synthesis. Uridine monophosphate synthase deficiency (or hereditary orotic aciduria), due to biallelic mutations in UMPS, is a rare condition presenting with megaloblastic anemia in the first months of life. If not treated with the pyrimidine precursor uridine, neutropenia, failure to thrive, growth retardation, developmental delay, and intellectual disability may ensue.Methods and resultsWe identified mild and isolated orotic aciduria in 11 unrelated individuals with diverse clinical signs and symptoms, the most common denominator being intellectual disability/developmental delay. Of note, none had blood count abnormalities, relevant hyperammonemia or altered plasma amino acid profile. All individuals were found to have heterozygous alterations in UMPS. Four of these variants were predicted to be null alleles with complete loss of function. The remaining variants were missense changes and predicted to be damaging to the normal encoded protein. Interestingly, family screening revealed heterozygous UMPS variants in combination with mild orotic aciduria in 19 clinically asymptomatic family members.ConclusionsWe therefore conclude that heterozygous UMPS-mutations can lead to mild and isolated orotic aciduria without clinical consequence. Partial UMPS-deficiency should be included in the differential diagnosis of mild orotic aciduria. The discovery of heterozygotes manifesting clinical symptoms such as hypotonia and developmental delay are likely due to ascertainment bias.