Chapter 062. Principles of Human Genetics (Part 7)

Transcriptional Activation and RepressionEvery gene is controlled uniquely, whether in its spatial or temporal pattern of expression or in its response to extracellular signals. It is estimated that transcription factors account for ~30% of expressed genes. A growing number of identified genetic diseases involve transcription factors (Table 62-2). The MODY (maturity-onset diabetes of the young) disorders are representative of this group of diseases; mutations in several different islet cell–specific transcription factors cause various forms of MODY (Chap. 338).Table 62-2 Selected Examples of Diseases Caused by Mutations and Rearrangements in Transcription Factor ClassesTranscription Factor ClassExampleAssociated DisorderNuclear receptorsAndrogen receptorComplete or partial...
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Chapter 062. Principles of Human Genetics (Part 7) Chapter 062. Principles of Human Genetics (Part 7) Transcriptional Activation and Repression Every gene is controlled uniquely, whether in its spatial or temporal patternof expression or in its response to extracellular signals. It is estimated thattranscription factors account for ~30% of expressed genes. A growing number ofidentified genetic diseases involve transcription factors (Table 62-2). The MODY(maturity-onset diabetes of the young) disorders are representative of this group ofdiseases; mutations in several different islet cell–specific transcription factorscause various forms of MODY (Chap. 338). Table 62-2 Selected Examples of Diseases Caused by Mutations andRearrangements in Transcription Factor Classes Transcription Example Associated DisorderFactor Class Nuclear Androgen Complete or partial androgenreceptors receptor insensitivity (recessive missense mutations) Spinobulbar muscular atrophy (CAG repeat expansion) Zinc finger WT1 WAGR syndrome: Wilmsproteins tumor, aniridia, genitourinary malformations, mental retardation Basic helix-loop- MITF Waardenburg syndrome typehelix 2A Homeobox IPF1 Maturity onset of diabetes mellitus type 4 (heterozygous mutation/haploinsufficiency) Pancreatic agenesis (homozygous mutation) Leucine zipper Retina Autosomal dominant retinitis leucine zipper pigmentosa (NRL) High mobility SRY Sex-reversalgroup (HMG) proteins Forkhead HNF4α, Maturity-onset of diabetes HNF1α, HNF1β mellitus types 1, 3, 5 Paired box PAX3 Waardenburg syndrome types 1 and 3 T-box TBX5 Holt-Oram syndrome (thumb anomalies, atrial or ventricular septum defects, phocomelia) Cell cycle P53 Li-Fraumeni syndrome, othercontrol proteins cancers Coactivators CREB Rubinstein-Taybi syndrome binding protein (CBP) General TATA- Spinocerebellar ataxia 17transcription factors binding protein (CAG expansion) (TBP) Transcription VHL Von Hippel–Lindau syndromeelongation factor (renal cell carcinoma, pheochromocytoma, pancreatic tumors, hemangioblastomas) Autosomal dominant inheritance, somatic inactivation of second allele (Knudson two-hit model) Runt CBFA2 Familial thrombocytopenia with propensity to acute myelogenous leukemia Chimeric PML— Acute promyelocyticproteins due to RAR leukemiat(15;17)(q22;q11.2-q12)translocations translocation Note: Selected abbreviations include: SRY, sex determining region Y;HNF, hepatocyte nuclear factor; CREB (cAMP responsive element binding)binding protein; VHL, Von Hippel–Lindau; PML, promyelocytic leukemia; RAR,retinoic acid receptor.