Diamond-Blackfan anaemia: genetic homogeneity for a gene on chromosome 19q13 restricted to 1.8 Mb

Abstract

Diamond-Blackfan anaemia (DBA; MIM#205900) is a rare disorder manifested as a pure red-cell aplasia in the neonatal period or in infancy. The clinical hallmark of DBA is a selective decrease in erythroid precursors and anaemia. Other lineages are usually normal and the peripheral white blood cell count is normal. In approximately one-third of cases, the disease is associated with a wide variety of congenital anomalies and malformations. Most cases are sporadic, but 10-20% of them follow a recessive or a dominant inheritance pattern. A female with DBA and a chromosomal translocation involving chromosome 19q was recently identified. We undertook a linkage analysis with chromosome 19 markers in multiplex DBA families of Swedish, French, Dutch, Arabic and Italian origin. Significant linkage to chromosome 19q13 was established for dominant and recessive inherited DBA with a peak lod score at D19S197 (Zmax = 7.08, theta = 0.00). Within this region, a submicroscopic de novo deletion of 3.3 Mb was identified in a patient with DBA. The deletion coincides with the translocation break-point and, together with key recombinations, restricts the DBA gene to a 1.8-Mb region. The results suggest that, despite its clinical heterogeneity, DBA is genetically homogeneous for a gene in 19q13.

Mutations in the ribosomal protein genes in Japanese patients with Diamond-Blackfan anemia

“…This gene is located at chromosome 19q13.2 and encodes a protein belonging to the small subunit of the ribosome. 9,10 Haploinsufficiency of the RPS19 gene product has been demonstrated in a subset of cases 11 and appears to be sufficient to cause DBA. The RPS19 protein plays an important role in 18S rRNA maturation and small ribosomal subunit synthesis in human cells.…”

What’s in a name?

“…WNTs signal via frizzled receptors to activate intracellular signaling pathways that lead to the stabilization of β-catenin (the socalled canonical pathway), or they stimulate various β-catenin-independent signals, like Ca 2+ influx or JNK activation (the noncanonical pathway) (1). Secreted frizzled-related proteins (SFRPs) containing cysteine-rich domains related to those of frizzled receptors negatively regulate WNT signaling by neutralizing WNTs extracellularly (2). WNT signaling has previously been reported to play an important role in adipocyte differentiation.…”

Mitochondrial ribosomal proteins: Candidate genes for mitochondrial disease

“…Although most cases of DBA are sporadic (approximately 75%), both dominant and autosomal recessive patterns of inheritance have been implicated in the remaining 25% of cases 30,36 -38 with dominant inheritance being more common. 39 In 1997, Gustavsson et al, 39 examined chromosome 19 for linkage to DBA after identifying a DBA patient with a balanced reciprocal translocation (X;19) (p21; q13). 39 (The X chromosome was excluded from consideration based on the observed autosomal transmission of DBA.)…”

“…39 In 1997, Gustavsson et al, 39 examined chromosome 19 for linkage to DBA after identifying a DBA patient with a balanced reciprocal translocation (X;19) (p21; q13). 39 (The X chromosome was excluded from consideration based on the observed autosomal transmission of DBA.) Subsequently, the region surrounding the (X;19) (p21; q13) translocation break point was cloned and sequenced allowing the identification of cytoplasmic ribosomal protein S19 (RPS19) as the gene disrupted by the translocation.…”