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FB2026_02
,
released June 18, 2026
This report describes Nil-Deshwar neurodevelopmental syndrome (NDNS), which has been associated with de novo missense mutations acting as autosomal dominants. The human gene implicated is DOT1L, which encodes DOT1-like histone lysine methyltransferase, an evolutionarily conserved histone lysine methyltransferase. There is one high-scoring fly ortholog, Dmel\gpp, for which multiple genetic reagents, including loss of function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis, have been generated.
Multiple UAS constructs of Hsap\DOT1L have been introduced into flies, both wild-type and variants associated with human disease. See the 'Disease-Implicated Variants' table below. Hsap\DOT1L variants behave as gain-of-function alleles and lead to increased H3K79 methylation levels. Expression of wild-type Hsap\DOT1L driven in the expression pattern of Dmel\gpp results in a lowered adult eclosion rate; this effect is more pronounced with mutant variants. Surviving adults exhibit wing defects, including wing vein defects and blistering; phenotypes induced by expression of mutant isoforms are more severe than those induced by wild-type Hsap\DOT1L.
Flies homozygous for loss-of-function alleles of Dmel\gpp exhibit developmental delay and a decrease of H3K79 methylation, and die during larval stages. Ubiquitous RNAi knockdown has similar results.
[updated Aug. 2025 by FlyBase; FBrf0222196]
[NIL-DESHWAR NEURODEVELOPMENTAL SYNDROME; NDNS](https://omim.org/entry/621265)
[DOT1-LIKE; DOT1L](https://omim.org/entry/607375)
Of 8 described patients, 8 had global developmental delay, which was described as severe in 4, 6 had feeding difficulties, and 4 patients had hypotonia. Speech and language delay was diagnosed in 7 patients where data was available; 2 patients were nonverbal. Variable congenital anomalies were observed. [from MIM:621265; 2025.07.30]
In a cohort of nine unrelated individuals, all had some degree of global developmental delay, with significant speech and language delays. Over half were found to have hypotonia. All individuals had congenital anomalies, with considerable heterogeneity across the cohort. These included brain structural anomalies, cardiac defects, urogenital features, ophthalmological features, and sensorineural hearing loss. (Nil, et al., 2023, pubmed:37827158; FBrf0257995).
Nil-Deshwan neurodevelopmental syndrome (NDNS) is caused by heterozygous mutation in the DOT1L gene. [from MIM:621265; 2025.07.30]
Neurodevelopmental disorder with global developmental delay, DOT1L-related has been associated with de novo missense variants resulting in a KMT (histone lysine methyltransferase) disorder through a gain-of-function mechanism (Nil, et al., 2023, pubmed:37827158; FBrf0257995).
Analysis of blood samples from several affected individuals suggest that there is a distinct DOT1L-specific methylation signature (Nil, et al., 2023, pubmed:37827158; FBrf0257995).
The protein encoded by the DOT1L gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes. [provided by RefSeq, Aug 2011]
One to one (1 human to 1 Drosophila); DOT1L has one high-scoring Drosophila ortholog, gpp.
High-scoring ortholog of human DOT1L (1 Drosophila to 1 human).