Analysis of short stature homeobox-containing gene (SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity

被引:35
作者
Grigelioniene, G [1 ]
Schoumans, J
Neumeyer, L
Ivarsson, SA
Eklöf, O
Enkvist, O
Tordai, P
Fosdal, I
Myhre, AG
Westphal, O
Nilsson, NÖ
Elfving, M
Ellis, I
Anderlid, BM
Fransson, I
Tapia-Paez, I
Nordenskjöld, M
Hagenäs, L
Dumanski, JP
机构
[1] Astrid Lindgrens Childrens Hosp, Paediat Endocrinol Unit Q208, S-17176 Stockholm, Sweden
[2] Karolinska Hosp, Paediat Endocrinol Unit, S-10401 Stockholm, Sweden
[3] Karolinska Hosp, Dept Mol Med, Clin Genet Unit, S-10401 Stockholm, Sweden
[4] Malmo Univ Hosp, Paediat Endocrinol Unit, Lund, Sweden
[5] Soder Hosp, Dept Hand Surg, Stockholm, Sweden
[6] Karolinska Hosp, Paediat Radiol Unit, S-10401 Stockholm, Sweden
[7] Visby Hosp, Dept Paediat, Visby, Sweden
[8] Akerhus Cent Hosp, Dept Paediat, Nordbyhagen, Norway
[9] Gothenburg Univ, Queen Silvias Children Hosp, Gothenburg, Sweden
[10] Halmstad Cty Hosp, Dept Paediat, Halmstad, Sweden
[11] Univ Lund Hosp, Paediat Clin, S-22185 Lund, Sweden
[12] Alder Hey Childrens Hosp, Dept Clin Genet, Liverpool L12 2AP, Merseyside, England
关键词
D O I
10.1007/s00439-001-0609-y
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Dyschondrosteosis (DCO; also called Leri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
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页码:551 / 558
页数:8
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