Novel PHF6 mutation p.D333del causes Borjeson-Forssman-Lehmann syndrome -: art. no. e50
Novel PHF6 mutation p.D333del causes Borjeson-Forssman-Lehmann syndrome -: art. no. e50
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DOI：
10.1136/jmg.40.4.e50
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发表时间：
2003-04-01
影响因子：
4
通讯作者：
Just, W
中科院分区：
文献类型：
--
作者：
Baumstark, A;Lower, KM;Just, W
X连锁精神发育迟滞组XLMR包括至少160种人类X染色体的综合征和非综合征病症，如在线人类孟德尔遗传目录（OMIM;登录日期2002年7月; http：ncbi. nlm。nih。gov/entrez/query。fcgi？（美国有线电视新闻网）db= OMIM）。对于其中的113个，基因位点已经被绘制出来，尽管基因本身可能还没有被识别出来。Börjeson-Forssman-Lehmann综合征（BFLS）1属于XLMR疾病的综合征形式。2 BFLS最好描述为精神缺陷-内分泌紊乱。这种相对罕见的疾病在1962年首次被描述。1其特征为中度至重度智力迟钝、面部脂肪过多、大耳朵、明显肥胖、性腺功能减退和男性乳房发育。详细的病理解剖随访的病人从第一次出版的综合征完成了彻底的描述表型。3虽然BFLS是一种X染色体重复性遗传疾病，但也可能见于女性，2 4可能是X失活偏斜的结果，甲基化特异性PCR已证实。5 BFLS受试者可能显示家族内和家族间表型变异。6还有其他常染色体和X连锁疾病具有相似的症状，使得BFLS的准确诊断更加困难。肥胖相关综合征的鉴别诊断包括Prader-Willi、Bardet-Biedl或Wilson-Turner综合征。然而，肥胖作为一个主要的症状是不一定与这些位点，如肥胖同胞的连锁分析证明。7因此，对表型进行彻底的分析是必要的。在BFLS中相当常见的一些特征，允许将这种疾病与其他精神发育迟滞/肥胖相关综合征区分开来：性腺功能减退、长而大的耳朵、突出的眶上嵴、长人中、突出的嘴唇、脊柱后凸、粗糙的面部和狭窄的睑裂，这些也被描述为眼睑下垂。8BFLS已通过连锁分析定位到染色体区域Xq 26-q27，在标记DXS 10和DXS 51之间具有最高lod得分。9-11候选基因区域后来通过包括额外的家族成员和该区域的改进的遗传图谱而得到改进。12然后计算标记物DXS 425和DXS 105之间的间隔的最高lod评分。靠近标记DXS 51的SOX 3基因13的定位刺激了在该SRY相关HMG盒基因中寻找突变。然而，发现SOX 3在BFLS患者中没有突变。12同时，已经鉴定了BFLS中的第一个突变基因。锌指蛋白PHF 6是通过BFLS候选基因区域的EST序列分析鉴定的。14 PHF 6基因（Genbank登录号：GI：27497548）在9个外显子中包含1095 bp的编码序列。ORF起始于外显子2，终止于外显子10。9个BFLS家系的PHF 6基因突变分析显示8个不同的突变，2个截短突变和6个错义突变。在外显子2中检测到三个突变，其中之一，p.C45Y，在两个家庭中检测到。在这份报告中，我们提出了一个新的家庭与BFLS与四个受影响的男性和四个女性运营商。我们
The X linked mental retardation group XLMR comprises at least 160 syndromic and non-syndromic disorders of the human X chromosome as summarised by the online catalogue of Mendelian inheritance in man (OMIM; accession date July 2002; http://www. ncbi. nlm. nih. gov/entrez/query. fcgi? db= OMIM). For 113 of these, the gene locus has been mapped, although the gene itself may not have been identified yet. Börjeson-Forssman-Lehmann syndrome (BFLS) 1 belongs to the syndromic forms of XLMR disorders. 2 BFLS is best described as a mental deficiency-endocrine disorder. This relatively rare disorder was described for the first time in 1962. 1 It is characterised by moderate to severe mental retardation, excessive facial fat, large ears, marked obesity, hypogonadism, and gynaecomastia. A detailed pathoanatomical follow up of the patient from the first publication of the syndrome completed the thorough description of the phenotype. 3 Although BFLS is an X chromosomal recessively inherited disorder, it may also be seen in women, 2 4 perhaps as a consequence of X inactivation skewing, as has been proven by methylation specific PCR. 5 Subjects with BFLS may show intra-and interfamilial phenotypic variability. 6 There are other autosomal and X linked disorders with similar symptoms, making the accurate diagnosis of BFLS more difficult. The differential diagnosis of obesity related syndromes includes syndromes like Prader-Willi, Bardet-Biedl, or Wilson-Turner syndromes. However, obesity as a cardinal symptom is not necessarily linked to these loci, as was proven by a linkage analysis of obese sibs. 7 Therefore, a thorough analysis of the phenotype is essential. Some features, which are quite frequent in BFLS and allow for the discrimination of this disorder from other mental retardation/obesity related syndromes are: hypogonadism, long, large ears, prominent supraorbital ridge, long philtrum, protruding lips, kyphosis, coarse face, and narrow palpebral fissures, which have been described also as lid ptosis. 8BFLS has been mapped by linkage analysis to the chromosomal region Xq26-q27 with the highest lod score between markers DXS10 and DXS51. 9–11 The candidate gene region was refined later by inclusion of additional family members and by an improved genetic map of this region. 12 The highest lod score was then calculated for the interval between the markers DXS425 and DXS105. The localisation of the SOX3 gene13 close to the marker DXS51 stimulated the search for mutations in this SRY related HMG box gene. It was found, however, that SOX3 has no mutations in patients with BFLS. 12 Meanwhile, a first gene mutated in BFLS has been identified. The zinc finger protein PHF6 was identified by a sequence analysis of ESTs in the BFLS candidate gene region. 14 The PHF6 gene (Genbank accession number: GI: 27497548) comprises 1095 bp of coding sequence in nine exons. The ORF starts in exon 2 and terminates in exon 10. The mutation analysis of PHF6 in nine families with BFLS showed eight different mutations, two truncation and six missense mutations. Three mutations were detected in exon 2 and one of these, p. C45Y, was detected in two families. In this report we present a new family with BFLS with four affected males and four female carriers. We