Identification of the first non‐Jewish mutation in familial Dysautonomia

Familial Dysautonomia is an autosomal recessive disease with a remarkably high carrier frequency in the Ashkenazi Jewish population. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease‐causing mutations have been identified. The most common mutation, which is present on 99.5% of all FD chromosomes, is an intronic splice site mutation that results in tissue‐specific skipping of exon 20. The second mutation, R696P, is a missense mutation that has been identified in 4 unrelated patients heterozygous for the major splice mutation. Interestingly, despite the fact that FD is a recessive disease, normal mRNA and protein are expressed in patient cells. To date, the diagnosis of FD has been limited to individuals of Ashkenazi Jewish descent and identification of the gene has led to widespread diagnostic and carrier testing in this population. In this report, we describe the first non‐Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L. This mutation is of particular significance because it was identified in a patient who lacks one of the cardinal diagnostic criteria for the disease–pure Ashkenazi Jewish ancestry. In light of this fact, the diagnostic criteria for FD must be expanded. Furthermore, in order to ensure carrier identification in all ethnicities, this mutation must now be considered when screening for FD. © 2003 Wiley‐Liss, Inc.

[1]  A. Aronheim,et al.  A Novel Specific Role for IκB Kinase Complex-associated Protein in Cytosolic Stress Signaling* , 2002, The Journal of Biological Chemistry.

[2]  R. Desnick,et al.  Familial dysautonomia: detection of the IKBKAP IVS20(+6T --> C) and R696P mutations and frequencies among Ashkenazi Jews. , 2002, American journal of medical genetics.

[3]  H. Erdjument-Bromage,et al.  Purification and Characterization of the Human Elongator Complex* , 2002, The Journal of Biological Chemistry.

[4]  J. Gusella,et al.  Cloning, characterization, and genomic structure of the mouse Ikbkap gene. , 2001, DNA and cell biology.

[5]  C Maayan,et al.  Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. , 2001, American journal of human genetics.

[6]  B. Rubin,et al.  Familial dysautonomia is caused by mutations of the IKAP gene. , 2001, American journal of human genetics.

[7]  A. Klippel,et al.  The IκB Kinase (IKK) Complex Is Tripartite and Contains IKKγ but Not IKAP as a Regular Component* , 2000, The Journal of Biological Chemistry.

[8]  Marc L. Mendillo,et al.  Precise genetic mapping and haplotype analysis of the familial dysautonomia gene on human chromosome 9q31. , 1999, American journal of human genetics.

[9]  P. Baeuerle,et al.  IKAP is a scaffold protein of the IκB kinase complex , 1998, Nature.

[10]  S. Godfrey,et al.  Incidence of familial dysautonomia in Israel 1977–1981 , 1987, Clinical genetics.

[11]  F. Guzzetta,et al.  Familial Dysautonomia in a Non‐Jewish Girl, with Histological Evidence ot Progression in the Sura l Nerve , 1986, Developmental medicine and child neurology.

[12]  J. Pearson,et al.  Congenital sensory neuropathies. Diagnostic distinction from familial dysautonomia. , 1984, American journal of diseases of children.

[13]  B. Wolf,et al.  Dysautonomia in an infant with secondary hyperammonemia due to propionyl coenzyme A carboxylase deficiency. , 1980, Pediatrics.

[14]  K. Mehta Familial dysautonomia in a Hindu boy. , 1978, American journal of diseases of children.

[15]  H. Ørbeck,et al.  FAMILIAL DYSAUTONOMIA IN A NON–JEWISH CHILD , 1977, Acta paediatrica Scandinavica.

[16]  P. Brunt,et al.  FAMILIAL DYSAUTONOMIA: A REPORT OF GENETIC AND CLINICAL STUDIES, WITH A REVIEW OF THE LITERATURE , 1970, Medicine.

[17]  Riley Cm,et al.  Central autonomic dysfunction with defective lacrimation; report of five cases. , 1949 .

[18]  H. Erdjument-Bromage,et al.  Elongator, a multisubunit component of a novel RNA polymerase II holoenzyme for transcriptional elongation. , 1999, Molecular cell.

[19]  M. Klebanoff,et al.  Familial dysautonomia associated with recurrent osteomyelitis in a non-Jewish girl. , 1980, The Journal of pediatrics.

[20]  P. Farrell,et al.  Familial dysautonomia: unusual presentation in an infant of non-Jewish ancestry. , 1977, The Journal of pediatrics.

[21]  K. Fujii,et al.  A case of new dysautonomia-like disorder found in Japan. I. Clinical and metabolic studies. , 1976, European neurology.

[22]  J. Dancis,et al.  Familial dysautonomia: diagnosis, pathogenesis and management. , 1974, Advances in pediatrics.