A family with autosomal dominant leukodystrophy linked to 5q23.2–q23.3 without lamin B1 mutations

Brussino, Alessandro; Vaula, Giovanna; Cagnoli, Claudia; Panza, Emanuele; Seri, Marco; Gregorio, Eleonora Di; Scappaticci, Susi; Camanini, Silvia; Daniele, D.; Bradac, Gianni Boris; Pinessi, Lorenzo; Cavalieri, Simona; Grosso, Enrico; Migone, Nicola; Brusco, Alfredo

doi:10.1111/j.1468-1331.2009.02844.x

Cited by 39 publications

(49 citation statements)

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“…In one instance, the LMNB1 duplication event involved recombination between Alu sequences, but most of the duplication events appeared to involve short (Ͻ6-bp) regions of homology upstream and downstream of LMNB1 (75). Interestingly, one family with clinical features of ADLD manifested lamin B1 overexpression without a gene duplication event, presumably from a LMNB1 regulatory abnormality (76).…”

Section: Lamin B1 Gene Duplications and Autosomal Dominant Leukodystrmentioning

confidence: 99%

Nuclear Lamins and Neurobiology

Young

Jung

Lee

et al. 2014

Molecular and Cellular Biology

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Much of the work on nuclear lamins during the past 15 years has focused on mutations in LMNA (the gene for prelamin A and lamin C) that cause particular muscular dystrophy, cardiomyopathy, partial lipodystrophy, and progeroid syndromes. These disorders, often called "laminopathies," mainly affect mesenchymal tissues (e.g., striated muscle, bone, and fibrous tissue). Recently, however, a series of papers have identified important roles for nuclear lamins in the central nervous system. Studies of knockout mice uncovered a key role for B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain. Also, duplications of LMNB1 (the gene for lamin B1) have been shown to cause autosome-dominant leukodystrophy. Finally, recent studies have uncovered a peculiar pattern of nuclear lamin expression in the brain. Lamin C transcripts are present at high levels in the brain, but prelamin A expression levels are very low-due to regulation of prelamin A transcripts by microRNA 9. This form of prelamin A regulation likely explains why "prelamin A diseases" such as Hutchinson-Gilford progeria syndrome spare the central nervous system. In this review, we summarize recent progress in elucidating links between nuclear lamins and neurobiology.T he nuclear lamina has attracted considerable scrutiny from biochemists, cell biologists, and geneticists. Much of this attention has been stimulated by the discovery that mutations in LMNA (the gene for the A-type lamins, prelamin A and lamin C) cause multiple human diseases, including muscular dystrophy, cardiomyopathy with conduction system disease, partial lipodystrophy, and progeroid syndromes (1-3). These diseases, often called "laminopathies," are largely confined to mesenchymal tissues. For the past decade, many laboratories have worked to define disease mechanisms and to devise therapeutic strategies. These efforts have been summarized in many reviews (2-11).While "LMNA diseases" have attracted most of the research efforts, a new topic has slowly emerged in the field-nuclear lamin biology in the brain. Three lines of investigation have contributed to the emergence of this topic. The first was work by developmental biologists that uncovered a role for the B-type lamins (lamins B1 and B2) in neuronal migration in the developing brain (12)(13)(14). The second was work showing that a demyelinating disorder, autosomal dominant leukodystrophy, is caused by LMNB1 gene duplications (15, 16). The third was work by clinical investigators to understand the spectrum of disease phenotypes in children with Hutchinson-Gilford progeria syndrome (17, 18), a precocious aging syndrome caused by a toxic form of prelamin A (19). For years, the field marveled that children with progeria have multisystem aging-like phenotypes but are spared common features of physiologic aging in the central nervous system, notably, senile dementia. Recent studies have identified a likely mechanismregulation of prelamin A by a brain-specific microRNA (17, 18). PROTEINS OF THE NUCLEAR LAMINAThe nuclear lamina...

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Section: Lamin B1 Gene Duplications and Autosomal Dominant Leukodystrmentioning

confidence: 99%

Nuclear Lamins and Neurobiology

Young

Jung

Lee

et al. 2014

Molecular and Cellular Biology

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“…In addition, later, ADLD has been reported in other population or ethnic groups including Italian, French-Canadian, Japanese, Swedish, and French (Asahara et al, 1996; Marklund et al, 2006; Melberg et al, 2006; Meijer et al, 2008; Brussino et al, 2009, 2010). But the Japanese family reported by Asahara et al (1996) was only diagnosis by clinical manifestations and the pattern of inheritance, the family didn’t undergo gene detection.…”

Section: Discussionmentioning

confidence: 98%

“…It has been described that a large Italian family with clinical symptoms similar with ADLD and molecular analysis showed that the disease was segregated with the LMNB1 locus, and over expression of LMNB1 mRNA and LMNB1 protein has been identified among all the affected family members. But comprehensive genetic analysis found that no alteration or copy number variation for LMNB1 gene (Brussino et al, 2010). …”

Section: Discussionmentioning

confidence: 99%

“…Generally, patients presented with autonomic dysfunction as a primary clinical symptom followed by loss of fine motor control or gait disturbances in the fourth or fifth decade of life (Schwankhaus et al, 1994; Coffeen et al, 2000). Various forms of bowel and bladder dysfunction along with sexual dysfunction are reported as the first presenting symptoms (Brussino et al, 2010). Similarly, our patient presented constipation as the first symptom around 50 years old.…”

Section: Discussionmentioning

confidence: 99%

“…In regard to movement problem, there are clinical variations in the reported family. The Italian kindred reported with ADLD were not presented with Ataxia (Brussino et al, 2010). Meijer et al (2008) reported in a French-Canadian kindred only manifested as slightly affected dysdiadochokinesis.…”

Section: Discussionmentioning

confidence: 99%

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An LMNB1 Duplication Caused Adult-Onset Autosomal Dominant Leukodystrophy in Chinese Family: Clinical Manifestations, Neuroradiology and Genetic Diagnosis

Dai

et al. 2017

Front. Mol. Neurosci.

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Autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) is a very rare neurological disorder featured with late onset, slowly progressive central nervous system demyelination. Duplication or over expression of the lamin B1 (LMNB1) gene causes ADLD. In this study, we undertook a comprehensive clinical evaluation and genetic detection for a Chinese family with ADLD. The proband is a 52-year old man manifested with autonomic abnormalities, pyramidal tract dysfunction. MRI brain scan identified bilateral symmetric white matter (WM) hyper-intensities in periventricular and semi-oval WM, cerebral peduncles and middle cerebellar peduncles. The proband has a positive autosomal dominant family history with similar clinical manifestations with a trend of genetic anticipation. In order to understand the genetic cause of the disease in this family, target exome capture based next generation sequencing has been done, but no causative variants or possibly pathogenic variants has been identified. However, Multiplex ligand-dependent probe amplification (MLPA) showed whole duplication of LMNB1 gene which is co-segregated with the disease phenotype in this family. This is the first genetically confirmed LMNB1 associated ADLD pedigree from China.

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