Neuronal apoptosis inhibitor protein, gene sequence and mutation

Details Neuronal apoptosis inhibitor protein, gene sequence and mutation Neuronal apoptosis inhibitor protein, gene sequence and mutation

1997-06-20

2000-02-01

Zitomer, Stephanie

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

435 71, 435 912, 536 231, 536 245, 536 2451, 536 2433, 530350, 5303871, 5303879, 53038815, 935 77, 935 78, C12Q 168, C12P 1934, G01N 3353, C07H 2104

Patent

active

060201274

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The gene for the neuronal apoptosis inhibitor protein (NAIP) has been identified in the q13 region of chromosome 5. Mutations in this gene have been diagnosed in individuals with Type I, II and III Spinal Muscular Atrophy. The amino acid sequence of the neuronal apoptosis inhibitor protein is provided and homology to viral apoptosis proteins demonstrated.


BACKGROUND OF THE INVENTION

In order to facilitate reference to various journal articles in the discussion of various aspects of this invention, a complete listing of the reference is provided at the end of the disclosure. Otherwise the references are identified in the disclosure by first author's name and publication year of the reference.
The childhood spinal muscular atrophies (SMAs) are a group of autosomal recessive, neurodegenerative disorders classified into three types based upon the age of onset and clinical progression (Dubowitz et al., 1978; Dubowitz et al., 1991). All three types are characterized by the degeneration of the alpha motor neurons of the spinal cord manifesting as weakness and wasting of the proximal voluntary muscles. Type I SMA is the most severe form with onset either in utero or within the first few months of life. Affected children are unable to sit unsupported and are prone to recurrent chest infections due to respiratory insufficiency, thus rarely surviving the first few years of life (Dubowitz et al., 1978; Dubowitz et al., 1991). This acute form, with a carrier frequency of 1/60 to 1/80, is one of the most frequent fatal autosomal recessive disorders. Affected children with Type II SMA never walk unaided and although the prognosis is variable, such children may die in adolescence. Those affected with Type III SMA maintain independent ambulation but develop weakness any time between the age of 3 to 17 years manifesting a mildly progressive course (Dubowitz et al., 1978; Dubowitz et al., 1991).
In 1990, all three childhood forms of SMA were genetically mapped to the long arm of chromosome 5 at 5q11.2-13.3 (Brustowitcz et al., 1990; Gilliam el al., 1990; Melki el al., 1990). Subsequent multi-point linkage analyses and the identification of recombinant events have further localized the genetic defect to the region flanked centromerically by D5S435/D5S629 (Soares et al., 1993; Wirth et al., 1993, Clermont et al., 1994)) and telomerically by MAP1B/D5S112 (Wirth et al., 1994; MacKenzie et al., 1993; Lien et al., 1991). This interval has been refined by the more recent identification of recombination events indicating that the SMA gene lies distal to CMS-1 (Yaraghi et al., submitted to Human Genetics; van der Steege, et al., submitted to Human Genetics) and proximal to D5S557 (Francis et al., 1993). We and others have detected chromosome 5-specific repetitive sequences with particular abundance in the D5S629/CMS-D5S557 region (Francis et al., 1993; Thompson et al., 1993) which has impeded the isolation and ordering of both clones and simple tandem repeats. An array of cosmid clones spanning the 200 kb CMS-1 (Kleyn et al., 1993)/CATT-1 (Burghes et al., 1994, McLean et al., in press)/D5F150/D5F149/D5F153 (Melki et al., 1994) region within this interval has been constructed.
We established a contiguous array of YAC clones encompassing the SMA containing D5S435-D5S112 interval of 5q13.1. We then discovered a gene within this interval of 5q13.1 which coded for a neuronal apoptosis inhibitor protein (NAIP). Further studies demonstrated that a deletion in this gene was found in Type I, II and III Spinal Muscular Atrophy.


SUMMARY OF THE INVENTION

A gene encoding a neuronal apoptosis inhibitor protein (NAIP) was discovered in the q13 region of human chromosome. According to an aspect of the invention, the cDNA sequence coding of the neuronal apoptosis inhibitor protein is provided and set out in Table 4 (SEQ ID NO: 1). According to another aspect of the invention, the predicted amino acid sequence of the neuronal apoptosis inhibitor protein is provided from the cDNA sequence.
According to another aspect of th

REFERENCES:
patent: 5882868 (1999-03-01), Funanage et al.
Soares et al.; "Refinement of the Spinal Muscular Atrophy Locus to the Interval between D5S435 and MAP1B"; Genomics, 15:365-371 (1993).
Francis et al.; "A contig of non-chimaeric YACs containing the spinal muscular atrophy gene in 5q13"; Human Molecular Genetics, 2(8):1161-1167 (1993).
Gilliam; "Is the Spinal Muscular Atrophy gene found?"; Nature Medicine, 1(2):124-127 (1995).
Roy et al.; "The Gene for Neuronal Apoptosis Inhibitory Protein is Partially Deleted in Individuals with Spinal Muscular Atrophy"; Cell 80:167-178 (1995).
Mahadevan et al.; "SMA genes: deleted and duplicated"; Nature Genetics, 9(2):112-113 (1995).
Shutler et al.; "Characterization of a cDNA clone that maps to the critical spinal muscular atrophy (SMA) locus region of 5q13"; Amer. J. of Human Genetics, 55(3):A327; Abstract #1919 (1994).

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