A novel 3-bp deletion in the PANK2 gene of Dutch patients with pantothenate kinase-associated neurodegeneration: evidence for a founder effect.

Mutation analysis was performed in four apparently unrelated Dutch families with pantothenate kinase-associated neurodegeneration, formerly known as Hallervorden-Spatz syndrome. A novel 3-bp deletion encompassing the nucleotides GAG at positions 1,142 to 1,144 of exon 5 of the PANK2 gene was found in all patients. One patient was compound heterozygous; she also carried a novel nonsense mutation (Ser68Stop).

Apparent gene conversions involving the SMN gene in the region of the spinal muscular atrophy locus on chromosome 5.

The survival motor neuron (SMN) gene has been described as a determining gene for spinal muscular atrophy (SMA). SMN has a closely flanking, nearly identical copy (cBCD541). Gene and copy gene can be discriminated by sequence differences in exons 7 and 8.

Prenatal prediction of spinal muscular atrophy. Experience with linkage studies and consequences of present SMN deletion analysis.

With the localisation of the gene for the autosomal recessive forms of proximal spinal muscular atrophies (SMA) to the chromosomal region 5q13 and the later detection of homozygous deletions of the SMN gene located in this region, prenatal prediction of SMA has become feasible and is widely applied now. In our experience with 77 prenatal predictions of SMA, follow-up of the 39 liveborn children from these pregnancies never led to a false-negative result. Application of SMN deletion analysis has consequences for prenatal prediction of SMA.

The physical map of the human RET proto-oncogene.

The RET proto-oncogene, a transmembrane tyrosine kinase receptor, is involved in the development of at least five different disease phenotypes. RET is activated through somatic rearrangements in a number of cases of papillary thyroid carcinoma while germ-line point mutations are associated with three inherited cancer syndromes MEN 2A, MEN 2B and FMTC. Moreover, point mutations or heterozygous deletions of RET are found in the dominant form of Hirschsprung disease or congenital colonic aganglionosis.

Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy.

DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type I. SMN deletions have not yet been described to occur in healthy subjects.

Expression of the human Dp 71 (apo-dystrophin-1) gene from a 760-kb DMD-YAC transferred to mouse cells.

A 760-kb YAC was constructed by homologous recombination in yeast, containing the genes located in the distal portion of the DMD gene. The YAC was introduced in mouse LA-9 cells by PEG-mediated cell fusion. One transformant accommodated an intact DMD-YAC, i.

A provisional transcript map of the spinal muscular atrophy (SMA) critical region.

YACs from the region containing the spinal muscular atrophy (SMA) locus at 5q12 have been used as probes in a direct screening of cDNA libraries to isolate 8 cDNAs, mapped to different YAC fragments. Three clones showed complete identity to the genes for cyclin B1 (CCNB1), the p44 subunit of the transcription factor BTF2 (BTF2p44), and cofilin (CFL). Two clones showed partial identity to the beta-glucuronidase gene (GLCB) and a rat integral membrane glycoprotein gene (RNINMEGLA).

Characterization and cell type distribution of a novel, major transcript of the Duchenne muscular dystrophy gene.

Previously we identified a novel 6.5 kb mRNA transcribed from the Duchenne muscular dystrophy (DMD) gene. This mRNA differs in coding content and tissue distribution from the known muscle type and brain type 14 kb DMD mRNAs which code for dystrophin.

Reconstruction of the 2.4 Mb human DMD-gene by homologous YAC recombination.

The human dystrophin gene, mutations of which cause Duchenne and Becker muscular dystrophy, measures 2.4 Mb. This size seriously limits its cloning as a single DNA fragment and subsequent in-vitro expression studies.

242 breakpoints in the 200-kb deletion-prone P20 region of the DMD gene are widely spread.

Using whole cosmids as probes, we have mapped 242 DMD/BMD deletion breakpoints located in the major deletion hot spot of the DMD gene. Of these, 113 breakpoints were mapped more precisely to individual restriction enzyme fragments in the distal 80 kb of the 170-kb intron 44. An additional 12 breakpoints are distributed over the entire region, with no significant local variation in frequency.

Topography of the Duchenne muscular dystrophy (DMD) gene: FIGE and cDNA analysis of 194 cases reveals 115 deletions and 13 duplications.

We have studied 34 Becker and 160 Duchenne muscular dystrophy (DMD) patients with the dystrophin cDNA, using conventional blots and FIGE analysis. One hundred twenty-eight mutations (65%) were found, 115 deletions and 13 duplications, of which 106 deletions and 11 duplications could be precisely mapped in relation to both the mRNA and the major and minor mutation hot spots. Junction fragments, ideal markers for carrier detection, were found in 23 (17%) of the 128 cases.

Familial X-linked myalgia and cramps: a nonprogressive myopathy associated with a deletion in the dystrophin gene.

We report a family with an X-linked recessive disorder characterized by muscle cramps and myalgia. Nine affected male family members had high resting serum levels of creatine kinase, and well-developed musculature with calf hypertrophy but no evidence of muscular weakness. Symptoms began in childhood and did not progress.

Germinal mosaicism increases the recurrence risk for 'new' Duchenne muscular dystrophy mutations.

In 288 Dutch and Belgian Duchenne and Becker muscular dystrophy families, the parental origin of 41 new deletion or duplication mutations was determined. Twenty seven of the new mutations occurred in the maternal X chromosome and nine in the grandmaternal and five in the grandpaternal X chromosome. The grandparental data are compatible with equal mutation rates for DMD in male and female X chromosomes.

High resolution deletion breakpoint mapping in the DMD gene by whole cosmid hybridization.

The locus DXS269 (P20) defines a deletion hotspot in the distal part of the Duchenne Muscular Dystrophy gene. We have cloned over 90 kilobase-pairs of genomic DNA from this region in overlapping cosmids. The use of whole cosmids as probes in a competitive DNA hybridization analysis proves a fast and convenient method for identifying rearrangements in this region.

Prenatal diagnosis of Duchenne muscular dystrophy: a three-year experience in a rapidly evolving field.

Application of molecular genetic techniques has greatly increased diagnostic possibilities of hereditary disorders. In 1983 the first linkage of Duchenne muscular dystrophy with flanking DNA probes was described, which made carrier detection possible in a limited number of cases. The first published prenatal diagnosis for Duchenne muscular dystrophy dates from 1985.

A deletion hot spot in the Duchenne muscular dystrophy gene.

We have made a detailed study of a deletion hot spot in the distal half of the Duchenne muscular dystrophy (DMD) gene, using intragenic probe P20 (DXS269), isolated by a hybrid cell-mediated cloning procedure. P20 detects 16% deletions in patients suffering from either DMD or Becker muscular dystrophy (BMD), in sharp contrast to the adjacent intragenic markers JBir (7%) and J66 (less than 1%), mapping respectively 200-320 kb proximal and 380-500 kb distal to P20. Of the P20 deletions, 30% start within a region of 25-40 kb, the majority extending distally.