Perez Yonatan, Kadir Rotem, Volodarsky Michael, Noyman Iris, Flusser Hagit, Shorer Zamir, Gradstein Libe, Birnbaum Ramon Y, Birk Ohad S
The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
Pediatric Neurology Unit, Division of Pediatrics, Faculty of Health Sciences, Soroka University Medical Center, Ben-Gurion University of the Negev, Beer Sheva, Israel.
J Med Genet. 2016 Jun;53(6):397-402. doi: 10.1136/jmedgenet-2015-103352. Epub 2015 Nov 6.
A syndrome of profound hypotonia, intellectual disability, intrauterine growth retardation with subsequent failure to thrive, dyskinesia and epilepsy was diagnosed in Bedouin Israeli families. Mild dysmorphism was evident: plagiocephaly, broad forehead with prominent nose, smooth philtrum and congenital esotropia. We set out to decipher the molecular basis of this syndrome.
Genome-wide linkage analysis and fine mapping were done. Whole exome sequencing data were filtered for candidate variants within locus. Validation and segregation of the mutation was assayed via Sanger sequencing. UNC80 expression pattern was analysed through reverse transcription PCR.
Homozygosity mapping followed by fine mapping identified a 7.5 Mb disease-associated locus (logarithm of odds score 3.5) on chromosome 2. Whole exome and Sanger sequencing identified a single homozygous nonsense mutation within this locus, segregating within the families as expected for recessive heredity and not found in a homozygous state in 150 Bedouin controls: c.151C>T, p.(R51*) in UNC80.
The syndrome described is caused by a mutation in UNC80, truncating most of the 3258 amino acids highly conserved encoded protein, that has no known motifs. UNC80 bridges between UNC79 and the cation channel NALCN, enabling NALCN's role in basal Na(+) leak conductance in neurons, essential for neuronal function. The phenotype caused by the UNC80 mutation resembles that previously described for homozygous NALCN mutations.
在以色列贝都因家庭中诊断出一种综合征，其特征为严重肌张力减退、智力残疾、宫内生长迟缓及随后的生长发育不良、运动障碍和癫痫。轻度畸形明显：斜头畸形、额头宽阔且鼻子突出、人中平滑和先天性内斜视。我们着手破解该综合征的分子基础。
进行了全基因组连锁分析和精细定位。对全外显子测序数据进行筛选以找出基因座内的候选变异。通过桑格测序法检测突变的验证和分离情况。通过逆转录聚合酶链反应分析UNC80的表达模式。
通过纯合性定位随后进行精细定位，在2号染色体上确定了一个7.5兆碱基的疾病相关基因座（优势对数得分3.5）。全外显子测序和桑格测序在该基因座内鉴定出一个纯合无义突变，在家族中按隐性遗传预期进行分离，且在15０名贝都因对照中未发现纯合状态：UNC80基因中的c.151C>T，p.(R51*)。
所描述的综合征由UNC80突变引起，该突变截断了由3258个氨基酸组成的高度保守的编码蛋白的大部分，该蛋白无已知基序。UNC80在UNC79和阳离子通道NALCN之间起桥梁作用，使NALCN在神经元基础钠（Na+）泄漏电导中发挥作用，这对神经元功能至关重要。UNC80突变引起的表型类似于先前描述的纯合NALCN突变的表型。
