Characterization of breakpoint sequences of five rearrangements in L1CAM and ABCD1 (ALD) genes

Mutations in L1CAM are responsible for X‐linked hydrocephalus, whereas those in the ALD gene (ABCD1) cause adrenoleukodystrophy. In both genes, most of the mutations reported so far are short‐length mutations and only a few patients with larger rearrangements have been documented. We have characterized three intragenic deletions of the ALD gene at the molecular level and describe here the first two L1CAM rearrangements resulting in deletion of several exons in one case and about 50 kb, including the entire gene, in the second case. At both breakpoints of an ALD deletion, Alu repeats have been found and, additionally, a short Alu region of ∼130 bp was inserted, suggesting that this rearrangement is the result of a more complex non‐allelic homologous recombination event. Only one Alu element was present at the breakpoint of the second ALD rearrangement, including a 26‐bp Alu core sequence that was suggested to be a recombinogenic hot spot. These data suggest the involvement of an Alu core sequence‐stimulated non‐homologous recombination as a possible cause for this rearrangement. Short direct repeats were identified at all putative mispaired sequences in the L1CAM breakpoints and at both breakpoints of the third ALD deletion characterized, suggesting non‐homologous (illegitimate) recombination as the molecular mechanism by which these latter deletions occurred. In conclusion, our results indicate that highly repetitive elements as well as short direct repeats are frequently involved in the formation of ALD and L1CAM gene rearrangements. Hum Mutat 19:526–535, 2002. © 2002 Wiley‐Liss, Inc.

[1]  H. Moser,et al.  ABCD1 mutations and the X‐linked adrenoleukodystrophy mutation database: Role in diagnosis and clinical correlations , 2001, Human mutation.

[2]  Tamim H. Shaikh,et al.  Segmental duplications: an 'expanding' role in genomic instability and disease , 2001, Nature Reviews Genetics.

[3]  J. V. Moran,et al.  Initial sequencing and analysis of the human genome. , 2001, Nature.

[4]  E. Eichler,et al.  Structure of chromosomal duplicons and their role in mediating human genomic disorders. , 2000, Genome research.

[5]  J. Schröder,et al.  Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. , 2000, American journal of medical genetics.

[6]  H. Soininen,et al.  Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer's disease family: an Alu core sequence-stimulated recombination? , 2000, European Journal of Human Genetics.

[7]  M. Batzer,et al.  Alu repeats and human disease. , 1999, Molecular genetics and metabolism.

[8]  K. Tavassoli,et al.  A deletion/insertion leading to the generation of a direct repeat as a result of slipped mispairing and intragenic recombination in the factor VIII gene , 1999, Human Genetics.

[9]  B. Burwinkel,et al.  Unequal homologous recombination between LINE-1 elements as a mutational mechanism in human genetic disease. , 1998, Journal of molecular biology.

[10]  J. Schröder,et al.  Molecular analysis of the L1CAM gene in patients with X-linked hydrocephalus demonstrates eight novel mutations and suggests non-allelic heterogeneity of the trait. , 1997, American journal of medical genetics.

[11]  J. Chae,et al.  Two partial deletion mutations involving the same Alu sequence within intron 8 of the LDL receptor gene in Korean patients with familial hypercholesterolemia , 1997, Human Genetics.

[12]  B. Royer-Pokora,et al.  A LINE element is present at the site of a 300-kb deletion starting in intron 10 of the PAX6 gene in a case of familial aniridia , 1996, Human Genetics.

[13]  R. Taramelli,et al.  Short direct repeats at the breakpoints of a novel large deletion in the CFTR gene suggest a likely slipped mispairing mechanism , 1996, Human Genetics.

[14]  Y. Suzuki,et al.  Mucopolysaccharidosis type IVA: common double deletion in the N-acetylgalactosamine-6-sulfatase gene (GALNS). , 1995, Genomics.

[15]  L. Peltonen,et al.  Deletion of the C-terminal end of aspartylglucosaminidase resulting in a lysosomal accumulation disease: evidence for a unique genomic rearrangement. , 1995, Human molecular genetics.

[16]  N. Gregersen,et al.  One short well conserved region of Alu-sequences is involved in human gene rearrangements and has homology with prokaryotic chi. , 1995, Nucleic acids research.

[17]  J. Mandel,et al.  Missense mutations are frequent in the gene for X-chromosomal adrenoleukodystrophy (ALD). , 1994, Human molecular genetics.

[18]  J. Mosser,et al.  Abnormal messenger RNA expression and a missense mutation in patients with X-linked adrenoleukodystrophy. , 1993, Human molecular genetics.

[19]  A. Munnich,et al.  A duplication in the L1CAM gene associated with X–linked hydrocephalus , 1993, Nature Genetics.

[20]  Jean Mosser,et al.  Putative X-linked adrenoleukodystrophy gene shares unexpected homology with ABC transporters , 1993, Nature.

[21]  E. Brinson,et al.  The 32·6 kb Indian δβ‐thalassaemia deletion ends in a 3·4 kb L1 element downstream of the β‐globin gene , 1992 .

[22]  K. Davies,et al.  Sequences of junction fragments in the deletion-prone region of the dystrophin gene. , 1991, Genomics.

[23]  R. Desnick,et al.  Alpha-galactosidase A gene rearrangements causing Fabry disease. Identification of short direct repeats at breakpoints in an Alu-rich gene. , 1990, The Journal of biological chemistry.

[24]  D. Mager,et al.  Molecular analysis of deletions in the human beta-globin gene cluster: deletion junctions and locations of breakpoints. , 1990, Genomics.

[25]  D. Higgs,et al.  Recombination at the human α-globin gene cluster: Sequence features and topological constraints , 1987, Cell.

[26]  D. Kioussis,et al.  Unexpected relationships between four large deletions in the human β-globin gene cluster , 1983, Cell.

[27]  A. George.  The metabolic basis of inherited disease , 1961 .

[28]  International Human Genome Sequencing Consortium.  Initial sequencing and analysis of the human genome , 2001, Nature.

[29]  R. Desnick,et al.  ar-Galactosidase A Gene Rearrangements Causing Fabry Disease , 2001 .

[30]  A. V. D. van den Ouweland,et al.  Characterisation of six large deletions in TSC 2 identified using long range PCR suggests diverse mechanisms including Alu mediated recombination , 2000 .

[31]  A. Ballabio,et al.  LINE-1 elements at the sites of molecular rearrangements in Alport syndrome-diffuse leiomyomatosis. , 1999, American journal of human genetics.

[32]  B. V. van Oost,et al.  Spectrum of mutations in the gene encoding the adrenoleukodystrophy protein. , 1995, American journal of human genetics.

[33]  E. Brinson,et al.  The 32.6 kb Indian delta beta-thalassaemia deletion ends in a 3.4 kb L1 element downstream of the beta-globin gene. , 1992, British Journal of Haematology.

[34]  F. Stahl.  Special sites in generalized recombination. , 1979, Annual review of genetics.