A family with autosomal dominant leukodystrophy linked to 5q23.2-q23.3 without lamin B1 mutations.
OBJECTIVE
Duplications of lamin B1 (LMNB1) at 5q23 are implicated in adult-onset autosomal dominant leukodystrophy (ADLD) having been described in six families with diverse ethnic background but with a homogeneous phenotype. In a large Italian family, we recently identified a variant form of ADLD characterized clinically by absence of the autonomic dysfunction at onset described in ADLD and, on MRI, by milder cerebellar involvement with sparing of hemispheric white matter. Aim of this study was to investigate the genetic basis of this variant form of ADLD.


METHODS
We carried out a genome-wide linkage analysis using microsatellite markers, and the genes in the candidate region were screened for point mutations. LMNB1 was also screened for deletions/duplications by real-time PCR, multiplex ligation-dependent probe amplification and Southern blot.


RESULTS
We mapped the variant ADLD locus to 5q23.2-q23.3, a genomic region containing 11 genes including LMNB1. Neither gene copy-number defects nor point mutations in the LMNB1 gene were found. We also excluded point mutations in the coding exons of the other ten genes in the candidate region. However, expression of lamin B1 evaluated in lymphoblastoid cells was higher in patients than in healthy controls, and was similar to the lamin B1 expression levels found in a patient with LMNB1 duplication.


CONCLUSIONS
This observation suggests that a mutation in an LMNB1 regulatory sequence underlies the variant ADLD phenotype. Thus, adult forms of ADLD linked to 5q23 appear to be more heterogeneous clinically and genetically than previously thought.
Brussino
A
A
Department of Genetics, Biology and Biochemistry, University of Torino, and SCDU.Medical Genetics, AOU San Giovanni Battista, Torino, Italy.
Vaula
G
G
Cagnoli
C
C
Panza
E
E
Seri
M
M
Di Gregorio
E
E
Scappaticci
S
S
Camanini
S
S
Daniele
D
D
Bradac
G B
GB
Pinessi
L
L
Cavalieri
S
S
Grosso
E
E
Migone
N
N
Brusco
A
A
D000328:Adult; D017668:Age of Onset; D000368:Aged; D002895:Chromosomes, Human, Pair 5; D056915:DNA Copy Number Variations; D005190:Family; D005260:Female; D020440:Gene Duplication; D008040:Genetic Linkage; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007558:Italy; D034921:Lamin Type B / Q000235:genetics* / Q000378:metabolism; D007965:Leukodystrophy, Globoid Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D017384:Sequence Deletion
D034921:Lamin Type B