GATA3 abnormalities and the phenotypic spectrum of HDR syndrome

Abstract

We report on GATA3 analysis and the phenotypic spectrum in nine Japanese families with the HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal dysplasia) (MIM 146255). Fluorescence in situ hybridisation and microsatellite analyses showed heterozygous gross deletions including GATA3 in four families. Sequence analysis showed heterozygous novel mutations in three families: a missense mutation within the first zinc finger domain at exon 4 (T823A, W275R), an unusual mutation at exon 4 (900insAA plus 901insCCT or C901AACCCT) resulting in a premature stop at codon 357 with loss of the second zinc finger domain, and a nonsense mutation at exon 6 (C1099T, R367X). No GATA3 abnormalities were identified in the remaining two families. The triad of HDR syndrome was variably manifested by patients with GATA3 abnormalities. The results suggest that HDR syndrome is primarily caused by GATA3 haploinsuYciency and is associated with a wide phenotypic spectrum. (J Med Genet 2001;38:374-380)

Molecular analysis of the GATA3 gene in five Japanese patients with HDR syndrome

“…The clinical characteristics of HDR syndrome are known to be heterogeneous among individuals [4,5,13,15]. Ferraris et al [5] have summarized the clinical presentations of patients described in the literature.…”

“…To date, gross deletions, missense mutations, nonsense mutations and small insertions or deletions (resulting in frameshifts) of GATA3 have been reported in human HDR syndrome [2,4,5,[11][12][13][14][15][16], and thus haploinsufficiency of GATA3 is the mechanism of HDR syndrome [11].…”

GATA3 haploinsufficiency causes a rapid deterioration of distortion product otoacoustic emissions (DPOAEs) in mice

“…Although it is clear that hearing loss in HDR is usually somewhat more severe at the higher end of the frequency spectrum Muroya et al, 2001), no systematic audiometric evaluation has yet been made, and the exact pathophysiological mechanism causing the hearing defect remains largely unknown. Genetically, HDR-syndrome is caused by haploinsufficiency of zinc finger transcription factor GATA3 (Van Esch and Bilous, 2001;Van Esch and Devriendt, 2001;Van Esch et al, 2000), which in mice is essential for development of several tissues and organs including the lymphatic system, the sympathetic nervous system, brain, kidney, jaw and inner ear (Lim et al, 2000;Pandolfi et al;, Pata et al, 1999Ting et al, 1996;van Doorninck et al, 1999;Zheng and Flavell, 1997).…”

“…The sensorineural hearing loss in HDR patients can be both symmetric or asymmetric, and as tested by auditory brainstem response (ABR), conditioned orientation reflex tests or pure tone audiometry, it ranges in level from 40 dB to 105 dB (Bilous et al, 1992;Fujimoto et al, 1999;Hasegawa et al, 1997;Lichtner et al, 2000;Muroya et al, 2001). Although it is clear that hearing loss in HDR is usually somewhat more severe at the higher end of the frequency spectrum Muroya et al, 2001), no systematic audiometric evaluation has yet been made, and the exact pathophysiological mechanism causing the hearing defect remains largely unknown.…”

An Uncommon Presentation of HDR Syndrome: Distal Renal Tubular Acidosis in a Patient with Sjögren’s Syndrome

“…Haploinsufficiency of GATA3 on chromosome 10p15 is implicated in the pathogenesis of the syndrome (2,3). Approximately two thirds of the patients present with the classic triad of hypoparathyroidism, sensorineural deafness and renal dysgenesis (4).…”