Chinese A gamma fetal hemoglobin: C to T substitution at position-196 of the A gamma gene promoter

Gelinas, Richard; Bender, Michael A.; Lotshaw, Carla; Waber, Pamela G.; Kazazian, Haig H.; Stamatoyannopoulos, George

doi:10.1182/blood.v67.6.1777.bloodjournal6761777

Cited by 39 publications

(1 citation statement)

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“… (Collins et al 1984 ; Gelinas et al 1986 ; Tate et al 1986 ; Waber et al 1986 ; Huang et al 1987 ; Pirastu et al 1987 ; Costa et al 1990 ; Fucharoen et al 1990 ; Oner et al 1991 ; Berry et al 1992 ; Lifton et al 1992 ; Loudianos et al 1992 ; Craig et al 1993 ; Zertal-Zidani et al 1999 ; Spitz et al 2002 ; Lettice et al 2002 ; Gurnett et al 2007 ; Smyk et al 2007 ; Otonkoski et al 2007 ; Furniss et al 2008 ; Sun et al 2008 ; Dathe et al 2009 ; Kurth et al 2009 ; Wieczorek et al 2010 ; Refai et al 2010 ; Dahlqvist et al 2010 ; Zhang et al 2010 ; Cox et al 2011 ; Pippucci et al 2011 ; Su et al 2011 ; Vetro et al 2011 ; Spielmann et al 2012 ; Allou et al 2012 ; Horn et al 2013 ; Lohan et al 2014 ; Giorgio et al 2014 ; Hazlewood et al 2015 ; Lupiáñez et al 2015 ; Davidson et al 2016 ; Ngcungcu et al 2017 ; Martyn et al 2018 ) …”

Section: Introductionunclassified

Functional categorization of gene regulatory variants that cause Mendelian conditions

Cheng,

Bohaczuk,

Stergachis

2024

Hum. Genet.

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Much of our current understanding of rare human diseases is driven by coding genetic variants. However, non-coding genetic variants play a pivotal role in numerous rare human diseases, resulting in diverse functional impacts ranging from altered gene regulation, splicing, and/or transcript stability. With the increasing use of genome sequencing in clinical practice, it is paramount to have a clear framework for understanding how non-coding genetic variants cause disease. To this end, we have synthesized the literature on hundreds of non-coding genetic variants that cause rare Mendelian conditions via the disruption of gene regulatory patterns and propose a functional classification system. Specifically, we have adapted the functional classification framework used for coding variants (i.e., loss-of-function, gain-of-function, and dominant-negative) to account for features unique to non-coding gene regulatory variants. We identify that non-coding gene regulatory variants can be split into three distinct categories by functional impact: (1) non-modular loss-of-expression (LOE) variants; (2) modular loss-of-expression (mLOE) variants; and (3) gain-of-ectopic-expression (GOE) variants. Whereas LOE variants have a direct corollary with coding loss-of-function variants, mLOE and GOE variants represent disease mechanisms that are largely unique to non-coding variants. These functional classifications aim to provide a unified terminology for categorizing the functional impact of non-coding variants that disrupt gene regulatory patterns in Mendelian conditions.

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Section: Introductionunclassified

Functional categorization of gene regulatory variants that cause Mendelian conditions

Cheng,

Bohaczuk,

Stergachis

2024

Hum. Genet.

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A frequent A?-persistence of fetal hemoglobin in northern Sardinia: its molecular basis and hematologic phenotype in heterozygotes and compound heterozygotes with ?-thalassemia

et al. 1988

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A survey of hemoglobinopathies in northern Sardinia revealed a high frequency (0.3%) of carriers of a hematologic condition characterized by increased expression of fetal hemoglobin during adult life (hereditary persistence of fetal hemoglobin or HPFH). In spite of a normal hematologic phenotype, the heterozygous carriers for this condition display about 12% HbF, almost exclusively of the A gamma type; compound heterozygotes with beta-thalassemia have 20%-26% HbF and run a very mild clinical course. The sequence analysis of the cloned A gamma gene linked to the HPFH determinant revealed the presence of a G----A substitution at position -117 of the A gamma-globin gene promoter; the same mutation occurs also in Greek HPFH, although associated with different restriction polymorphisms. Another hereditary condition characterized by increased HbF (alpha 2 A gamma 2) level and a mild thalassemia phenotype in Sardinia is associated with the -196C----T substitution in the A gamma-globin gene promoter (Sardinian delta beta-thalassemia). Population studies using oligonucleotides complementary both to the -117 G----A and -196C----T mutations and the corresponding normal sequences confirm the presence of these mutations only in HPFH and delta beta-thalassemia chromosomes and exclude these changes being common DNA polymorphisms.

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Hemoglobin F production in heterocellular hereditary persistence of fetal hemoglobin and its linkage to the ? globin gene complex

1988

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Some types of nondeletional heterocellular hereditary persistence of fetal hemoglobin (HPFH) appear to be caused by mutations in the beta globin gene cluster near the gamma globin genes, while in other cases the condition is associated with a gene or genes outside the beta globin gene complex. We have used DNA probes for chromosome 11 markers to localize the HPFH determinant in a large Australian kindred with nondeletional heterocellular HPFH. In 13 of the 58 family members studied the Hb F levels are increased to between 1.8% and 7.9%, the Hb F being composed predominantly of A gamma chains. All family members were typed for restriction fragment length polymorphisms detected by probes from the beta globin gene complex, and the nearby genetic markers D11S12, INS, and HRAS. Linkage analysis showed HPFH is closely linked to the beta globin gene cluster (confidence limits of theta, 0.0-0.19), D11S12 (theta, 0.0-0.23) and the insulin gene (theta, 0.0-0.11). These data and the gamma chain composition are consistent with HPFH in this family being caused by a mutation within the beta globin gene cluster.

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Chinese A gamma fetal hemoglobin: C to T substitution at position-196 of the A gamma gene promoter

Cited by 39 publications

References 0 publications

Functional categorization of gene regulatory variants that cause Mendelian conditions

Functional categorization of gene regulatory variants that cause Mendelian conditions

A frequent A?-persistence of fetal hemoglobin in northern Sardinia: its molecular basis and hematologic phenotype in heterozygotes and compound heterozygotes with ?-thalassemia

Hemoglobin F production in heterocellular hereditary persistence of fetal hemoglobin and its linkage to the ? globin gene complex

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