During the last quarter of the twentieth century, our knowledge about human genetic variation was limited mainly to the heterochromatin polymorphisms, large enough to be visible in the light microscope, and the single nucleotide polymorphisms (SNPs) identified by traditional PCR-based DNA sequencing. In the past five years, the rapid development and expanded use of microarray technologies, including oligonucleotide array comparative genomic hybridization and SNP genotyping arrays, as well as next-generation sequencing with “paired-end” methods, has enabled a whole-genome analysis with essentially unlimited resolution. The discovery of submicroscopic copy-number variations (CNVs) present in our genomes has changed dramatically our perspective on DNA structural variation and disease. It is now thought that CNVs encompass more total nucleotides and arise more frequently than SNPs. CNVs, to a larger extent than SNPs, have been shown to be responsible for human evolution, genetic diversity between individuals,...

Structural Variation in the Human Genome and its Role in Disease

Amyotrophic lateral sclerosis (ALS) is a paralytic disorder caused by motor neuron degeneration. Mutations in more than 50 human genes cause diverse types of motor neuron pathology. Moreover, defects in five Mendelian genes lead to motor neuron disease, with two mutations reproducing the ALS phenotype. Analyses of these genetic effects have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Here, we present an overview of the mechanisms for motor neuron death and of the role of non-neuronal cells in ALS.

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Molecular biology of amyotrophic lateral sclerosis: insights from genetics.

DNA deletion associated with hereditary neuropathy with liability to pressure palsies

Pseudoxanthoma elasticum (PXE) is a heritable disorder of the connective tissue. PXE patients frequently experience visual field loss and skin lesions, and occasionally cardiovascular complications1,2,3,4. Histopathological findings reveal calcification of the elastic fibres and abnormalities of the collagen fibrils5. Most PXE patients are sporadic, but autosomal recessive and dominant inheritance are also observed6,7. We previously localized the PXE gene to chromosome 16p13.1 (refs 8,9) and constructed a physical map10. Here we describe homozygosity mapping in five PXE families and the detection of deletions or mutations in ABCC6 (formerly MRP6) associated with all genetic forms of PXE in seven patients or families.

/pdf/mutations-in-abcc6-cause-pseudoxanthoma-elasticum-459p3uxykp.pdf

Mutations in ABCC6 cause pseudoxanthoma elasticum.

Summary Charcot–Marie–Tooth disease is the most common inherited neuromuscular disorder. There have been substantial advances in elucidating the molecular bases of this genetically heterogeneous neuropathy and, in most cases, molecular diagnosis is now possible. The diagnostic approach requires careful assessment of clinical presentation and mode of inheritance, nerve-conduction studies, and DNA testing, and current research is focused on assessing natural history and finding effective treatments. Disease course is variable because of genotypic and phenotypic heterogeneity. At present, there is no drug therapy for Charcot–Marie–Tooth disease, and rehabilitation therapy and surgical procedures for skeletal deformities are the only available treatments, although best practice has not been defined. Animal models are proving useful for the identification of therapeutic targets and approaches. Progesterone antagonists, neurotrophic factors, ascorbic acid, and curcumin have shown promising results in experimental models, and ascorbic acid is being studied in large randomised controlled trials.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70110-3.pdf

Diagnosis, natural history, and management of Charcot–Marie–Tooth disease

De-novo mutation in hereditary motor and sensory neuropathy type I.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder of the peripheral nerves leading to increased susceptibility to mechanical traction or compression. Some patients have been shown to be carriers of a 1.5-Mb deletion in chromosome 17p11.2, which corresponds to the duplicated region present in most patients with Charcot-Marie-Tooth disease type 1A. Recently, evidence has been presented that the deletion is not the only cause of HNPP. To determine the prevalence of the 1.5-Mb deletion, we have examined 22 unrelated families with HNPP in the following two ways: by polymerase chain reaction analysis of marker loci D17S122 and D17S261, and by gene dosage measurements with DNA probes for D17S122 (VAW409R3a) and D17S125 (VAW412R3a) and for the PMP-22 gene. The efficiency and sensitivity of these methods is discussed. Our results show that the prevalence of the 17p deletion in our families with HNPP is 68%. One patient, presenting as a sporadic case, was found to be affected by a de novo deletion in the paternal chromosome. Single-strand conformation analysis of the protein-coding region of the PMP-22 gene did not reveal any mutation in patients from the 7 families lacking the 17p deletion. As a group, these families could not be distinguished by clinical, electrophysiological, or morphological features from the families with the deletion.

Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is a disorder of the peripheral nervous system, the cause of which has recently been identified as a deletion on chromosome 17p. The deletion corresponds to the duplication that is commonly observed in patients with hereditary motor and sensory neuropathy type Ia (HMSNIa, 17p11.2–p12). Therefore, the gene for peripheral myelin protein 22 (PMP-22) is a candidate gene for both HMSNIa and HNPP. Here, we show that a similar deletion is present in one family with HNPP but is clearly absent in another family. Affected members of this family carry the expected two copies of the PMP-22 gene and the surrounding region. Furthermore, linkage analyses of this family exclude a large part of 17p, spanning the area deleted in other families with HNPP, as the location for the disease gene. These data strongly argue for the existence of genetic heterogeneity underlying HNPP. Results from two-point linkage analysis with markers on chromosome 1q are inconsistent with a possible involvement of the locus for HMSNIb in the present family.

Evidence for genetic heterogeneity underlying hereditary neuropathy with liability to pressure palsies

The most frequently found mutation in autosomal dominant hereditary motor and sensory neuropathy type I (HMSN I) is a large duplication on chromosome 17p11.2 containing probes VAW409R3, VAW412R3, and EW401. We investigated a family with severe features of HMSN I, and demonstrated the absence of this duplication by a quantitative analysis of the hybridization signals of VAW409R3 and VAW412R3. Linkage analysis, however, revealed linkage with probe VAW409R3a (lod score, 3.22), which demonstrates the existence of allelic heterogeneity within the HMSN Ia locus. These findings have implications for clinical practice and for investigating the identity of the HMSN Ia gene.

F. J. M. Gabreëls

Papers

De-novo mutation in hereditary motor and sensory neuropathy type I.

Prevalence of the 1.5-Mb 17p deletion in families with hereditary neuropathy with liability to pressure palsies.

Evidence for genetic heterogeneity underlying hereditary neuropathy with liability to pressure palsies

Allelic heterogeneity in hereditary motor and sensory neuropathy type Ia (Charcot-Marie-Tooth disease type 1a)

Hereditary motor and sensory neuropathies