A novel cDNA detects homozygous microdeletions in greater than 50% of type I spinal muscular atrophy patients

Abstract

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disease in Caucasians (after cystic fibrosis). Childhood SMAs are divided into three groups (type I, II and III), which are allelic variants of the same locus in a region of approximately 850 kb in chromosome 5q12-q13, containing multiple copies of a novel, chromosome 5-specific repeat as well as many atypical pseudogenes. This has hampered the identification of candidate genes. We have identified several coding sequences unique to the SMA region. A genomic fragment detected by one cDNA is homozygously deleted in 17/29 (58%) of type I SMA patients. Of 235 unaffected individuals examined, only two showed the deletion and both are carriers of SMA. Our results suggest that deletion of at least part of this novel gene is directly related to the phenotype of SMA.

Expressed cadherin pseudogenes are localized to the critical region of the spinal muscular atrophy gene.

“…This is the case with several human diseases such as Gaucher, 21-hydroxylase deficiency, CharcotMarie-Tooth type 1A, and defects with visual pigment genes (1)(2)(3)38). Such an assumption coincides well with finding that deletions in the SMA region occur at extremely high rates (7,14,17,19,20), reaching almost 100% for SMN, one of the SMA candidate genes (18).…”

“…polyadenylylated transcripts. We believe that these transcripts represent a class of unusually transcribed pseudogenes from the SMA region which are similar in their organization and expression to transcripts derived from two of the SMA candidate genes (19,20). In addition, the genomic organization of c41-cad and Br-cadherin sheds light on the origin of repetitive sequences in the SMA locus.…”

“…The repetitive nature and unusual instability of this region hindered the task of narrowing down the critical region and identifying candidate genes (7,8,(14)(15)(16)(17). However, deletions of several regional polymorphic markers in SMA patients (7,9) led to the discovery of three candidate genes, all present in multiple copies and exhibiting homozygous deletions in SMA patients at very high rates (18)(19)(20).…”

Inactivation of the survival motor neuron gene, a candidate gene for human spinal muscular atrophy, leads to massive cell death in early mouse embryos

“…Positional cloning strategies and deletion analysis have led to the identification of three candidate genes for spinal muscular atrophy, survival motor neuron SMN (10), neuronal apoptosis inhibitory protein NAIP (11), and transcript XS2G3 (12) [corresponding to exon 7 of the NAIP gene in reverse orientation (13)]. All these candidate genes are positioned within a complex region that is duplicated on the long arm of chromosome 5 (14), resulting in two copies of the NAIP and the SMN gene in the human genome.…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…A growing number of examples include Prader-Willi syndrome/Angelman syndrome (15q11-13), Williams-Beuren syndrome (7q11), spinal muscular atrophy (5q12-13), neurofibromatosis type 1 (NF1) (17q11), Smith-Magenis syndrome (17p11) and Sotos syndrome (5q35). [10][11][12][13][14][15][16] DS22 arises at a frequency of 1 in 3000 live births including a high incidence of de novo cases. Indeed, PCR detects frequent de novo deletions in sperm from healthy donors.…”