This report describes neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (NEDMLOB). NEDMLOB exhibits autosomal recessive inheritance. The human gene implicated in this disease is INTS11, which encodes the integrator complex subunit 11 of the Integrator complex. There is one high-scoring fly ortholog, Dmel\IntS11, for which genetic reagents such as RNAi-targeting constructs and alleles caused by insertional mutagenesis have been generated.
A UAS construct of the wild-type human Hsap\INTS11 gene has been introduced into flies. Overexpression of wild-type Hsap\INTS11 does not affect viability or cause an obvious phenotype; nor does it rescue lethality associated with Dmel\IntS11 loss of function mutations.
Variants implicated in human disease (as analogous mutations in fly gene IntS11) have been studied in flies; two (R17L and H414Y) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Five variants (G55S, L138F, p.K396E, V517M, and I553E) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants (FBrf0256463). See the 'Disease-Implicated Variants' table below.
Loss of function alleles of Dmel\IntS11 exhibits developmental delay and are lethal at the second larval instar. Glial-specific RNAi-knockdown of IntS11 is semi-lethal; adult escapers have a shortened lifespan and impaired climbing ability (FBrf0256463).
[updated Mar. 2024 by FlyBase; FBrf0222196]
[NEURODEVELOPMENTAL DISORDER WITH MOTOR AND LANGUAGE DELAY, OCULAR DEFECTS, AND BRAIN ABNORMALITIES; NEDMLOB](https://omim.org/entry/620428)
[INTEGRATOR COMPLEX SUBUNIT 11; INTS11](https://omim.org/entry/611354)
A cohort of 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy (Tepe, et al., 2023, pubmed:37054711; FBrf0256463).
Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (NEDMLOB) is an autosomal recessive neurologic disorder characterized by the onset of features in infancy or early childhood. Affected individuals show hypotonia, severe motor delay with ataxic gait or sometimes an inability to achieve walking, and impaired intellectual development with speech and language delay. Ocular defects can include optic atrophy, nystagmus, strabismus, and retinal dystrophy. Additional features may include seizures (in some), dysmorphic facial features, poor overall growth, and variable brain imaging abnormalities (Tepe et al., 2023, pubmed:37054711; FBrf0256463). [from MIM:620428; 2023.07.11]
Neurodevelopmental disorder with impaired motor development and brain atrophy, INTS11-related results from homozygous or bi-allelic mutation in the gene encoding integrator complex subunit 11 (INTS11) (Tepe, et al., 2023, pubmed:37054711; FBrf0256463).
Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (NEDMLOB) is caused by homozygous or compound heterozygous mutation in the INTS11 gene on chromosome 1p36. [from MIM:620428; 2023.07.11]
The Integrator complex contains at least 12 subunits and associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A) and mediates the 3-prime end processing of small nuclear RNAs U1 (RNU1) and U2 (RNU2). INTS11, or CPSF3L, is the catalytic subunit of the Integrator complex (Baillat et al., 2005, pmid:16239144). [from MIM:611354; 2023.06.02]
One to one (1 human to 1 Drosophila); INTS11 has one high-scoring Drosophila ortholog, IntS11.
High-scoring ortholog of human INTS11, (1 Drosophila to 1 human).
