Tandem duplication of the NF1 gene detected by high-resolution FISH in the 17q11.2 region

The gene for neurofibromatosis type 1 (NF1), mapping to 17q11.2, has one of the highest observed mutation rates, partially because of its large size and gene conversion primed by NF1 pseudogenes. We have previously shown by means of high resolution fluorescence in situ hybridization (FISH) that a number of the loci flanking the NF1 gene are duplicated, in agreement with the reported presence of NF1 repetitive sequences (REPs). We report a direct tandem duplication of the NF1 gene identified in 17q11.2 by high-resolution FISH. FISH on stretched chromosomes with locus-specific probes revealed the duplication of the NF1 gene from the promoter to 3'UTR, but with at least the absence of exon 22. Fiber FISH with P1 artificial and bacterial artifical chromosomes, including the NF1 5'UTR and 3'UTR and flanking regions, visualized the direct tandem duplication with a similar, but not identical, genomic organization of the NF1 duplicon copies. Duplication was probably present in the human-chimpanzee-gorilla common ancestor, as demonstrated here by the finding of the duplicated NF1 gene at orthologous chromosome loci. The NF1 intrachromosomal duplication may contribute to the high whole-gene mutation rate by gene conversion, although the functional activity of the NF1 copy remains to be investigated. Detection of the NF1 duplicon by high-resolution FISH may pave the way to filling the gaps in the human genomic sequence of the pericentromeric 17q11.2 region.     

Molecular characterisation of t(17;22)(q11.2;q11.2) is not consistent with NF1 gene duplication

A tandem duplication of the NF1 gene in 17q11.2 has recently been detected by high-resolution fluorescence in situ hybridisation (FISH) on stretched chromosomes and DNA fibres. These findings suggest not only that, in the 17q11.2 region, the NF1 gene is surrounded by NF1 low-copy repeats on each side of the gene, but also that the NF1 gene and its directly flanking regions are duplicated structures. However, if the NF1 gene is duplicated at 17q11.2, this should be observed by FISH analysis on metaphase chromosomes of relevant translocation carriers with the probes originally used to identify the duplication, since hybridisation signals of some of the probes would be expected on both derivative chromosomes, the der(17) and the der(22). We have only been able to obtain signals on the one or the other derivative of a female translocation carrier. Therefore, our results do not support the hypothesis of a duplication of the NF1 gene and its immediately flanking regions at 17q11.2 as had been previously postulated. Rather, our findings suggest that there is one NF1 gene in the 17q11.2 region.     

Characterization of a cytogenetic 17q11.2 deletion in an NF1 patient with a contiguous gene syndrome

We report on a rare patient screened as a putative carrier of a contiguous gene syndrome on the basis of a complex phenotype characterized by sporadic neurofibromatosis type 1 (NF1), dysmorphism, mental retardation and severe skeletal anomalies. A cytogenetically visible 17q11.2 deletion was detected in the patient’s karyotype by high-resolution banding and confirmed by fluorescence in situ hybridization with yeast artificial chromosomes targeting the NF1 region. Analysis of the segregation from parents to proband of 13 polymorphic DNA markers, either contiguous or contained within the NF1 gene, showed that the patient is hemizygous at sites within the NF1 gene – the AAAT-Alu repeat in the 5′ region of intron 27b, the CA/GT microsatellite in the 3′ region of intron 27b, and the CA/GT microsatellite in intron 38 – and at the extragenic D17S798 locus, distal to the 3′ end of NF1. The patient may be an important resource in the identification of genes downstream of NF1 that may contribute to some of his extra-NF1 clinical signs. Received: 8 May 1996 / Revised: 17 June 1996     

A third neurofibromatosis type 1 (NF1) pseudogene at chromosome 15q11.2

Sequences related to the neurofibromatosis type 1 (NF1) gene have been identified on several human chromosomes. In the centromeric region of chromosomes 14 and 15, two NF1 pseudogenes have been described. Sequence comparison between NF1-related exons amplified from two yeast artificial chromosome clones hybridizing to chromosomal region 15q11.2 and published NF1-related sequences localized at 15q11.2 suggested that a third NF1 pseudogene resides in this chromosomal region. The previous localization of an NF1-related locus to the telomeric part of chromosome 15 could not be confirmed by us. Our findings further support pericentromeric spreading of partial NF1 gene copies at chromosome 15q11.2 during evolution. Received: 27 January 1996 / Accepted: 26 May 1997     

Partial trisomy 17q and monosomy 9p due to a familial translocation.

Described is an infant with partial trisomy 17q and monosomy 9p [46,XX,-9,+der(9)t(9;17)(p21;q23)] due to adjacent-1 segregation of a maternal balanced reciprocal translocation. Characteristic clinical features of both partial 17q trisomy and monosomy 9p are present, but the former syndrome is less recognisable in this infant than in previously reported cases due to the concomitant 9p monosomy.     

Localization of monocyte chemotactic protein-1 gene (SCYA2) to human chromosome 17q11.2-q21.1

Monocyte chemotactic protein-1 (MCP-1) is a member of the small inducible gene (SIG) family. It has been shown to play a role in the recruitment of monocytes to sites of injury and infection. By analysis of a panel of somatic cell hybrids, we have localized the MCP-1 gene, designated SCYA2, to human chromosome 17. In situ hybridization confirmed this assignment and further localized the gene to 17q11.2-q21.1.     

Congenital hyperthyroidism with reciprocal translocation t(1;17)(q25;q21)

Summary The authors report a case of 1;17 translocation and request contact with colleagues who have observed similar cases.