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General Information
Name
leukodystrophy, demyelinating, adult-onset, autosomal dominant
FlyBase ID
FBhh0000873
Overview

This report describes 'leukodystrophy, demyelinating, adult-onset, autosomal dominant' (ADLD), also called 'autosomal dominant adult-onset leukodystrophy' and 'autosomal dominant leukodystrophy with autonomic disease'. This disease is most commonly associated with a heterozygous tandem genomic duplication resulting in an extra copy of the lamin B1 gene (LMNB1). Lamins are intermediate filaments that are major components of the nuclear lamina on the interior of the nuclear envelope. There are multiple lamins in both humans and flies: the human genes LMNA, LMNB2 and LMNB1 are orthologous to fly genes Dmel\Lam and Dmel\LamC. Classical amorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for both fly genes.

A UAS construct of the wild-type human Hsap\LMNB1 gene has been introduced into flies. Overexpression of the human gene in different neural tissues results in phenotypes similar to, but much milder than, those observed for overexpression of the Drosophila Lam gene.

The original determination that ADLD can be caused by duplication of the human LMNB1 was supported by work in Drosophila characterizing overexpression phenotypes of Dmel\Lam. Overexpression in the developing eye results in neuroanatomical defects and a neurodegenerative phenotype; pan-neuronal overexpression of Dmel\Lam results in lethality. Many physical and genetic interactions of Dmel\Lam have been described; see below and in the Lam gene report.

[updated Aug. 2018 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: leukodystrophy, demyelinating, adult-onset, autosomal dominant
OMIM report
[LEUKODYSTROPHY, DEMYELINATING, ADULT-ONSET, AUTOSOMAL DOMINANT; ADLD](http://omim.org/entry/169500)
Human gene(s) implicated
[LAMIN B1; LMNB1](http://omim.org/entry/150340)
Symptoms and phenotype
Autosomal dominant leukodystrophy with autonomic disease (ADLD) is a slowly progressive disorder of central nervous system white matter characterized by onset of autonomic dysfunction in the fourth to fifth decade, followed in months to years by pyramidal and cerebellar involvement. [Gene Reviews, Autosomal Dominant Leukodystrophy with Autonomic Disease; 2018.08.20]
Autosomal dominant adult-onset demyelinating leukodystrophy is a slowly progressive and fatal disorder that presents in the fourth or fifth decade of life and is characterized clinically by early autonomic abnormalities, pyramidal and cerebellar dysfunction, and symmetric demyelination of the CNS. [from OMIM:169500; 2018.08.20]
Genetics
Most cases of autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) are caused by a heterozygous tandem genomic duplication resulting in an extra copy of the lamin B1 gene (LMNB1). [from OMIM:169500; 2018.08.20]
Cellular phenotype and pathology
Molecular information
LMNB1 encodes one of the two B-type lamin proteins in human; lamins are components of the nuclear lamina. [Gene Cards, LMNB1; 2018.08.20]
Lamin B, a component of the interphase nuclear lamina, is required to maintain nuclear shape and mechanical integrity (Goldman et al., 2002; pubmed:11877373). [from OMIM:150340; 2018.08.20]
External links
Disease synonyms
autosomal dominant adult-onset demyelinating leukodystrophy
ADLD
adult-onset demyelinating leukodystrophy
leukodystrophy, adult-onset, autosomal dominant
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
Symbol / Name
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)
Many to many: 3 human to 2 Drosophila. The human genes LMNA, LMNB2 and LMNB1 are orthologous to fly genes Dmel\Lam and Dmel\LamC.
Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    In progress.Contributions welcome.
    Gene Groups / Pathways
    Comments on ortholog(s)
    Moderate-scoring ortholog of human genes LMNA, LMNB2 and LMNB1 (2 Drosophila to 3 human). Dmel\Lam shares 36-37% identity and 57-60% similarity with the human genes.
    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Synthetic Gene(s) Used (0)
    Summary of Physical Interactions (29 groups)
    protein-protein
    Interacting group
    Assay
    References
    two hybrid, cosedimentation, western blot, inferred by author
    anti bait coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, anti tag western blot
    two hybrid, pull down, western blot
    two hybrid, experimental knowledge based
    pull down, anti tag western blot, anti bait coimmunoprecipitation, western blot, ion exchange chromatography, peptide massfingerprinting, anti tag coimmunoprecipitation
    anti bait coimmunoprecipitation, peptide massfingerprinting
    experimental knowledge based
    pull down, western blot, two hybrid, anti bait coimmunoprecipitation
    solid phase assay, anti bait coimmunoprecipitation, western blot, autoradiography
    anti bait coimmunoprecipitation, western blot, two hybrid
    experimental knowledge based
    anti bait coimmunoprecipitation, anti tag western blot, affinity chromatography technology, Identification by mass spectrometry
    anti bait coimmunoprecipitation, western blot
    two hybrid, anti tag coimmunoprecipitation, western blot, experimental knowledge based, anti bait coimmunoprecipitation
    affinity chromatography technology, Identification by mass spectrometry
    pull down, western blot, affinity chromatography technology, Identification by mass spectrometry
    experimental knowledge based
    experimental knowledge based
    anti bait coimmunoprecipitation, Identification by mass spectrometry
    anti tag coimmunoprecipitation, comigration in sds page, anti tag western blot
    experimental knowledge based
    anti bait coimmunoprecipitation, western blot, two hybrid
    anti tag coimmunoprecipitation, anti tag western blot
    pull down, western blot, anti bait coimmunoprecipitation, proximity ligation assay
    pull down, western blot
    RNA-protein
    Interacting group
    Assay
    References
    anti bait coimmunoprecipitation, quantitative reverse transcription pcr
    Alleles Reported to Model Human Disease (Disease Ontology) (0 alleles)
    Genetic Tools, Stocks and Reagents
    Sources of Stocks
    Contact lab of origin for a reagent not available from a public stock center.
    Bloomington Stock Center Disease Page
    Selected mammalian transgenes
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila transgenes
    Allele
    Transgene
    Publicly Available Stocks
    RNAi constructs available
    Allele
    Transgene
    Publicly Available Stocks
    Selected Drosophila classical alleles
    Allele
    Allele class
    Mutagen
    Publicly Available Stocks
    loss of function allele
    P-element activity
    amorphic allele - genetic evidence
    P-element activity
    loss of function allele
    ethyl methanesulfonate
    amorphic allele - genetic evidence
    P-element activity
    loss of function allele
    X ray
    loss of function allele
    X ray
    loss of function allele
    ethyl methanesulfonate
    loss of function allele
    X ray
    References (5)