Human Cancer Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
Orphanet J Rare Dis. 2012 Aug 28;7:56. doi: 10.1186/1750-1172-7-56.
Inherited malabsorption of cobalamin (Cbl) causes hematological and neurological abnormalities that can be fatal. Three genes have been implicated in Cbl malabsorption; yet, only about 10% of ~400-500 reported cases have been molecularly studied to date. Recessive mutations in CUBN or AMN cause Imerslund-Gräsbeck Syndrome (IGS), while recessive mutations in GIF cause Intrinsic Factor Deficiency (IFD). IGS and IFD differ in that IGS usually presents with proteinuria, which is not observed in IFD. The genetic heterogeneity and numerous differential diagnoses make clinical assessment difficult.
We present a large genetic screening study of 154 families or patients with suspected hereditary Cbl malabsorption. Patients and their families have been accrued over a period spanning >12 years. Systematic genetic testing of the three genes CUBN, AMN, and GIF was accomplished using a combination of single strand conformation polymorphism and DNA and RNA sequencing. In addition, six genes that were contenders for a role in inherited Cbl malabsorption were studied in a subset of these patients.
Our results revealed population-specific mutations, mutational hotspots, and functionally distinct regions in the three causal genes. We identified mutations in 126/154 unrelated cases (82%). Fifty-three of 126 cases (42%) were mutated in CUBN, 45/126 (36%) were mutated in AMN, and 28/126 (22%) had mutations in GIF. We found 26 undescribed mutations in CUBN, 19 in AMN, and 7 in GIF for a total of 52 novel defects described herein. We excluded six other candidate genes as culprits and concluded that additional genes might be involved.
Cbl malabsorption is found worldwide and genetically complex. However, our results indicate that population-specific founder mutations are quite common. Consequently, targeted genetic testing has become feasible if ethnic ancestry is considered. These results will facilitate clinical and molecular genetic testing of Cbl malabsorption. Early diagnosis improves the lifelong care required by these patients and prevents potential neurological long-term complications. This study provides the first comprehensive overview of the genetics that underlies the inherited Cbl malabsorption phenotype.
遗传性钴胺素（Cbl）吸收不良会导致血液和神经系统异常，严重者可致命。目前已有 3 个基因与 Cbl 吸收不良相关，但迄今为止，仅有约 10%的~400-500 例报告病例进行了分子研究。CUBN 或 AMN 的隐性突变导致 Imerslund-Gräsbeck 综合征（IGS），而 GIF 的隐性突变导致内因子缺乏（IFD）。IGS 和 IFD 的不同之处在于，IGS 通常表现为蛋白尿，而 IFD 则没有。遗传异质性和众多鉴别诊断使得临床评估变得困难。
我们对 154 个疑似遗传性 Cbl 吸收不良的家族或患者进行了大规模的基因筛查研究。患者及其家属在过去 12 年以上的时间里被纳入研究。采用单链构象多态性和 DNA 及 RNA 测序相结合的方法对 CUBN、AMN 和 GIF 这三个基因进行系统的基因检测。此外，我们还在这些患者的亚组中研究了六个候选基因在遗传性 Cbl 吸收不良中的作用。
我们的研究结果揭示了三个致病基因中存在群体特异性突变、突变热点和功能不同的区域。我们在 154 个无关联病例中的 126 例（82%）中发现了突变。CUBN 突变 53 例（42%），AMN 突变 45 例（36%），GIF 突变 28 例（22%）。我们在 CUBN 中发现了 26 个未描述的突变，在 AMN 中发现了 19 个，在 GIF 中发现了 7 个，共描述了 52 个新的缺陷。我们排除了其他 6 个候选基因作为致病基因，并得出结论认为可能还有其他基因参与其中。
Cbl 吸收不良在世界各地均有发现，且遗传情况较为复杂。然而，我们的研究结果表明，群体特异性的创始突变相当常见。因此，如果考虑到种族背景，有针对性的基因检测变得可行。这些结果将有助于 Cbl 吸收不良的临床和分子遗传检测。早期诊断可改善这些患者终生所需的护理，并预防潜在的神经长期并发症。本研究提供了对遗传性 Cbl 吸收不良表型相关遗传基础的全面概述。
