Fine mapping of the locus for Shwachman-Diamond syndrome at 7q11, identification of shared disease haplotypes, and exclusion of TPST1 as a candidate gene

Abstract

Shwachman-Diamond syndrome (SDS) is an autosomal recessive disorder characterised by exocrine pancreatic dysfunction, haematological and skeletal abnormalities. We have previously defined the SDS locus as a 2.7 cM interval spanning the centromere of chromosome 7. To facilitate additional analysis of this complex and poorly characterised region, a framework of ordered genetic markers at 7p11-q11, including six newly identified, has been constructed using somatic cell, radiation hybrid and STS-content mapping. We have identified shared disease haplotypes, that recur in unrelated families of common ethnic origin, and extend across the SDS locus. Detection of ancestral and intrafamilial recombination events in patients refined the SDS locus to a 1.9 cM interval at 7q11, which contains the tyrosylprotein sulfotransferase 1 (TPST1) gene. Patients with SDS were screened for mutations in TPST1 by sequencing of exons and intron ± exon junctions. Two single nucleotide polymorphisms, but no disease-causing mutations, were identified. In addition, Southern blot analysis yielded no evidence of large-scale mutations, and RT ± PCR analysis failed to detect alterations in expression. These results exclude TPST1 as the causative gene for SDS. The established map of the refined SDS locus will assist in the identification and characterisation of other candidate genes for SDS.

Genetic Analysis of Shwachman-Diamond Syndrome: Phenotypic Heterogeneity in Patients Carrying Identical SBDS Mutations

“…Cytogenetic studies of bone marrow aspirates from SDS patients who developed myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) more frequently showed structural abnormalities of chromosome 7q as compared to MDS without SDS (Smith et al 1995;Smith et al C and 183-184 (Goobie et al 2001;Popovic et al 2002;Boocock et al 2003). Most mutations detected in the patients are introduced by gene conversion between SBDS and its highly homologous pseudogene (SBDSP).…”

Huntingtin-interacting protein 1-related is required for accurate congression and segregation of chromosomes

“…This observation may be helpful in uncovering important new aspects of how HIP1 family proteins affect cell proliferation and the survival of diverse types of cells. Chromosomal mutations of the HIP1 and HIP1r genes occur in various genetic syndromes (20,21). Given the evidence that HIP1r functions in mitosis, HIP1r may be primarily required for chromosome integrity, which is essential for cell viability, speciation, birth defects, cancer, or human disease.…”

“…HIP1 was also found to be part of a chromosomal translocation with PDGFbR in myelomonocytic leukemia with t(5;7)(q33;q11.2) (19). The chromosomal locus of 7q11 for HIP1 (12q for HIP1r) was deleted and mutated in human patients with various genetic syndromes (20,21). Chromosomal alterations such as mutations and deletions usually occur when there is an error in cell division following meiosis or mitosis.…”

Hematologically important mutations: Shwachman–Diamond syndrome

“…Other systemic findings (skeletal, liver and psychomotor) and/or problems secondary to bone marrow dysfunction may also be detected [1][2][3][4]. Intermittent or persistent neutropenia is the most common hematologic finding, but anemia and thrombocytopenia can also been present in approximately 40% of the patients [1][2][3][4][5].…”

“…This gene, designated SBDS (Shwachman-Bodian-Diamond syndrome), is composed of five exons spanning 7.9 kb. The authors also described a pseudogene (SBDSP; MIM# 607444), with 97% homology to SBDS [5][6][7]. SBDS comprises five exons spanning 7.9 kb, with a 1.6 kb transcript that translates into a protein of 250 amino acids [6,7].…”