TUBA8 mutations in polymicrogyria syndrome
Polymicrogyria is a disorder of brain development, in which the cerebral cortical gyri are replaced by numerous excessively small convolutions. Eamonn Sheridan and colleagues have studied individuals with a distinctive combination of polymicrogyria and optic nerve hypoplasia. The disorder was mapped to Chr. 22q11.2 and homozygous mutations demonstrated in TUBA8, an evolutionarily divergent member of the alpha-tubulin gene family. Tubulins and other microtubule-related components are important for correct cortical neuronal migration, being implicated in inherited lissencephalies (smooth brain). The new findings implicate a tubulin of hitherto unknown function in the process of cerebral cortical organization.
Abdollahi MR, Morrison E, Sirey T, Molnar Z, Hayward BE, Carr IM, Springell K, Woods CG, Ahmed M, Hattingh L, Corry P, Pilz DT, Stoodley N, Crow Y, Taylor GR, Bonthron DT, Sheridan E (2009) Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. Am J Hum Genet 85:737-44. Journal website
Autozygosity mapping using unaffected individuals
The mapping of lethal recessive disorders is sometimes hampered by lack of access to DNA from affected individuals who have died. Colin Johnson, Ian Carr and colleagues have developed an approach to map such disorders by using genetic data from unaffected family members. This strategy, “shadow autozygosity mapping by linkage exclusion” (SAMPLE), allows identification of candidate regions of the genome for further study. For further detail, see the SAMPLE web page.
Carr IM, Szymanska K, Sheridan E, Markham AF, Bonthron DT, Johnson CA (2009) Shadow autozygosity mapping by linkage exclusion (SAMPLE): A simple strategy to identify the genetic basis of lethal autosomal recessive disorders Hum Mutation 10.1002/humu.21105. Journal website
Aicardi-Goutières gene highlights new immune regulator
Yanick Crow (now at the University of Manchester) and colleagues at the Centre for Autozygosity mapping report the identification of SAMHD1 as the fifth gene for Aicardi-Goutières syndrome. This disorder results from constitutive activation of cellular innate immunity. The new finding suggests that SAMHD1, like TREX1 and RNAseH2, prevents activation of innate immunity by endogenous cellular components.
Rice GI, Bond J, Asipu A, Brunette RL, Manfield IW, Carr IM, Fuller JC, Jackson RM, Lamb T, Briggs TA, Ali M, Gornall H, Couthard LR, Aeby A, Attard-Montalto SP, Bertini E, Bodemer C, Brockmann K, Brueton LA, Corry PC, Desguerre I, Fazzi E, Cazorla AG, Gener B, Hamel BC, Heiberg A, Hunter M, van der Knaap MS, Kumar R, Lagae L, Landrieu PG, Lourenco CM, Marom D, McDermott MF, van der Merwe W, Orcesi S, Prendiville JS, Rasmussen M, Shalev SA, Soler DM, Shinawi M, Spiegel R, Tan TY, Vanderver A, Wakeling EL, Wassmer E, Whittaker E, Lebon P, Stetson DB, Bonthron DT, Crow YJ (2009) Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nature Genet 41:829-32. Nature Genetics site
Cone-rod dystrophy gene identified
Chris Inglehearn and colleagues have used autozygosity mapping to identify a new gene for recessive cone-rod dystrophy. The findings implicate the metalloprotease ADAM9 in this disorder, and led to the demonstration of similar defects in the Adam9 knockout mouse, which now represents a valuable therapeutic model for this form of inherited blindness.
Parry DA, Toomes C, Bida L, Danciger M, Towns KV, McKibbin M, Jacobson SG, Logan CV, Ali M, Bond J, Chance R, Swendeman S, Daniele LL, Springell K, Adams M, Johnson CA, Booth AP, Jafri H, Rashid Y, Banin E, Strom TM, Farber DB, Sharon D, Blobel CP, Pugh EN Jr, Pierce EA, Inglehearn CF (2009) Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice. Am J Hum Genet 84:683-691. Journal site
Potassium channel involved in epilepsy and renal function
With colleagues at the Institute of Child Health, Eamonn Sheridan, Sally Feather and Angus Dobbie have characterized a new autosomal recessive syndrome of epilepsy, ataxia, deafness, and renal tubulopathy. Their studies show that the condition results from mutation of the potassium channel gene KCNJ10, expressed in the inner ear, brain and kidney. The findings are reported in the New England Journal of Medicine.
Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Arora R, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009) Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. N Engl J Med 360:1960-70. NEJM site
Glaucoma gene identified
In primary congenital glaucoma (PCG), abnormally high intraocular pressure (IOP) is present within the first year of life. This can lead to optic nerve damage, globe enlargement, and permanent loss of vision. Manir Ali, Chris Inglehearn and colleagues have recently identified LTBP2 on Chr. 14q24.3 as a new gene for this autosomal recessive condition. LTBP2 is a large protein containing TGF-β-binding protein-like modules, which also interacts with fibrillin. The identification of LTBP2 as a glaucoma gene gives new insights into the possible roles of these molecules in development of the ciliary body and surrounding structures.
Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, Gilmour DF, Towns K, Murphy A, Azmanov D, Tournev I, Cherninkova S, Jafri H, Raashid Y, Toomes C, Craig J, Mackey DA, Kalaydjieva L, Riazuddin S, Inglehearn CF (2009). Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 84:664-671. Journal site
Eye-tooth disease gene identified
Jalili syndrome is a recessively inherited disorder in which amelogenesis imperfecta causes severe loss of dental enamel, and a cone-rod dystrophy with macular atrophy occurs. By autozygosity mapping, the group of Chris Inglehearn, Alan Mighell and colleagues have shown that Jalili syndrome results from mutations of the CNNM4 gene which encodes a putative metal ion transporter.
Parry DA, Mighell AJ, El-Sayed W, Shore RC, Jalili IK, Dollfus H, Bloch-Zupan A, Carlos R, Carr IM, Downey LM, Blain KM, Mansfield DC, Shahrabi M, Heidari M, Aref P, Abbasi M, Michaelides M, Moore AT, Kirkham J, Inglehearn CF (2009). Mutations in CNNM4 cause Jalili syndrome, consisting of autosomal-recessive cone-rod dystrophy and amelogenesis imperfecta. Am J Hum Genet 84:266-73. Journal site
New tool for mutation detection
Rapid screening of DNA sequence traces for the presence of mutations is facilitated by GeneScreen, a freely available Windows program specifically aimed at human disease gene identification and diagnostic mutation scanning. GeneScreen was written by Ian Carr. A preview version is available for download.
Clubbing gene identified
Primary hypertrophic osteoarthropathy (PHO), also known as pachydermoperiostosis, is a mendelian inherited form of finger clubbing, the familiar clinical sign that usually occurs secondary to lung cancer, cyanotic congenital heart disease, or any of a host of other serious pathological processes. By autozygosity mapping, the group of Chris Bennett, David Bonthron and colleagues have shown that PHO is a disorder of prostaglandin metabolism, caused by deficiency of the enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD). These findings give insight into the likely role of prostaglandins in mediating secondary clubbing.
Uppal S, Diggle CP, Carr IM, Fishwick CWG, Ahmed M, Ibrahim GH, Helliwell PS, Latos-Bielenska A, Phillips SEV, Markham AF, Bennett CP, Bonthron DT (2008) Mutations in 15-hydroxyprostaglandin dehydrogenase cause primary hypertrophic osteoarthropathy. Nature Genet 40:789–783 (doi:10.1038/ng.153).
Nature Genetics website
