Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1997-01-29
2000-03-21
Myers, Carla J.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 912, 435 915, 536 235, 536 2431, 536 2433, C07H 2104, C12Q 168, C12P 1934
Patent
active
060401427
DESCRIPTION:
BRIEF SUMMARY
Infantile spinal muscular atrophy (SMA) represents the commonest group of fatal autosomal recessive hereditary disorders after cystic fibrosis (incidence: 1/6,000) (1). SMA is characterized by a degeneration of the motor neurones of the anterior horn of the spinal cord, leading to a progressive paralysis of the limbs and trunk associated with a muscular atrophy. Infantile spinal muscular atrophy is divided into categories termed types I, II and III, according to the age of onset of the symptoms and the manner of their progression (2).
It should be noted that type I spinal muscular atrophy is observed only in newborn babies and in infants: it is the most serious type, the life expectancy of these children barely exceeding a few years.
Type II spinal muscular atrophy also manifests itself as early as the first year of life of the children affected, but after they have acquired the ability to sit. They can then barely get up any longer,. and at best reach the stage of adolescence.
Lastly, type III spinal muscular atrophy appears in children when they begin to walk; the symptoms described above then develop more slowly.
Apart from diagnosis based on clinical and paraclinical signs (electromyography and muscle biopsy) of appearance of the disease, signs which often do not afford the requisite specificity, there hardly exist any other methods permitting an equivalent diagnosis, be it only in a limited number of cases. It goes without saying that the clinician, called upon to anticipate the future appearance of the disease in patients presumed to be at risk or, in neonatal medicine, in the fetus, is even more helpless.
The biochemical abnormality of this disorder is unknown. Nevertheless, the gene responsible for the three forms of SMA has been localized by genetic linkage analysis on chromosome 5q11.2-q13.3 (3-6), so that the disorders in question would appear to be alleleic.
Recently, the gene responsible for SMA has been localized on chromosome 5 within a span of 2 centimorgans (cM) defined by the flanking loci D5S629 and D5S637 (7).
Several fragments originating from this chromosome have been cloned in yeast artificial chromosomes or YACs. Several contigs of YACs of the 5q13 region have been described. The expression "contig of the 5q13 region" relates to a set of YACs in which the inserts formed from fragments of the 5q13 region may be considered to overlap one another, this set of fragments nevertheless spanning the whole of the 5q13 region. One of these contigs consisted of 7 overlapping YACs covering approximately 3.2 Mb (13), the other of 10 overlapping YACs covering a region of 2 Mb (14). However, none of the markers known to date enables a correlation to be established, be it only partial yet reliable, between the detection which can be performed using them and the clinical signs of the disease.
The invention is based more especially on the discovery that the 5q13 region contained several loci which, setting aside repeat sequences which varied in number, possessed substantially identical nucleotide sequences and formed a similar number of polymorphic markers characteristic of this region. The polymorphism of these markers is the source of the capacity of researchers to distinguish between them, to correlate them sometimes with those carried by the parents of the subjects under study, or on the contrary to identify the de novo character of the mutations or deletions to which they may be subjected. This polymorphism is also the source of the capacity now possessed by researchers in a number of cases, either to find therein the confirmation of the correct nature of a clinical diagnosis of SMA, in particular of type 1, or sometimes to rule it out, for example in neonatal medicine and when there is a history of the disease in a brother or sister.
These new DNA markers, more especially polymorphic markers (microsatellites), were identified by screening fragments contained within the abovementioned span of two cM identified by (7) and contained in a YAC of 4 Mb. This screening was performed by employing a lib
REFERENCES:
Brahe et al. American Journal of Medical Genetics. 45:408-411, 1993.
Brahe et al. Human Genetics. 93:494-501, May 1994.
Burghes et al. Genomics. 21:394-402, May 1994.
Wirth et al, "Large Linkage Analysis in 100 Families with Autosomal Recessive Spinal Muscular Atrophy (SMA) and 11 CEPH Families Using 15 Polymorphic Loci in the Region 5q11.2-q13.3", Genomics 20:84-93 (1994).
Clermont et al, "Use of Genetic and Physical Mapping to Locate the Spinal Muscular Atrophy Locus between Two New Highly Polymorphic DNA Markers", Am. J. Hum. Genet. 54:687-694 (1994).
Brzustowicz et al, "Paternal Isodisomy for Chromosome 5 in a Child with Spinal Muscular Atrophy", Am. J. Hum. Genet. 54:482-488 (1994).
Thompson et al, "High resolution physical map of the region surrounding the spinal muscular atrophy gene", Human Molecular Genetics 2(8):1169-1176 (1993).
Huschenbett et al, "Prenatal Diagonosis of the Acute Form of Proximal Spinal Muscular Atrophy: Experience on the Acceptance of Linkage Analyses by the Families", Prenatal Diagnosis 13:643 (1993).
Melki et al, "De Novo and Inherited Deletions of the 5q13 Region in Spinal Muscular Atrophies", Science 264:1474-1477 (1994).
Melki Judith
Munnich Arnold
Institut National de la Santa et de la Recherche Medicale
Myers Carla J.
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