Meier–Gorlin syndrome genotype–phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis

Abstract

Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, patellar aplasia/hypoplasia, and short stature. Recently, mutations in five genes from the pre-replication complex (ORC1, ORC4, ORC6, CDT1, and CDC6), crucial in cell-cycle progression and growth, were identified in individuals with MGS. Here, we report on genotype-phenotype studies in 45 individuals with MGS (27 females, 18 males; age 3 months-47 years). Thirty-five individuals had biallelic mutations in one of the five causative pre-replication genes. No homozygous or compound heterozygous null mutations were detected. In 10 individuals, no definitive molecular diagnosis was made. The triad of microtia, absent/hypoplastic patellae, and short stature was observed in 82% of individuals with MGS. Additional frequent clinical features were mammary hypoplasia (100%) and abnormal genitalia (42%; predominantly cryptorchidism and hypoplastic labia minora/majora). One individual with ORC1 mutations only had short stature, emphasizing the highly variable clinical spectrum of MGS. Individuals with ORC1 mutations had significantly shorter stature and smaller head circumferences than individuals from other gene categories. Furthermore, compared with homozygous missense mutations, compound heterozygous mutations appeared to have a more severe effect on phenotype, causing more severe growth retardation in ORC4 and more frequently pulmonary emphysema in CDT1. A lethal phenotype was seen in four individuals with compound heterozygous ORC1 and CDT1 mutations. No other clear genotype-phenotype association was observed. Growth hormone and estrogen treatment may be of some benefit, respectively, to growth retardation and breast hypoplasia, though further studies in this patient group are needed. (MIM 224690) is a form of primordial dwarfism, characterized by microtia, short stature, and absent or hypoplastic patellae. Furthermore, pulmonary emphysema, feeding problems, various skeletal abnormalities, genitourinary anomalies, and mammary hypoplasia frequently accompany this autosomal recessive disorder. Characteristic facial features, which gradually change with age, are frequently described. Infants typically have a small mouth with full lips and micrognathia, whereas in adults, a high forehead and a more prominent, narrow nose with a broad nasal bridge are distinguishable.The first patient was reported by Meier in 1959. 1 Gorlin reported the second patient with a similar phenotype. 2 In total, only 53 cases have been described in the literature thus far. Recently, mutations in ORC1, a pre-replication complex member gene, were identified in 5 out of 204 individuals with microcephalic primordial dwarfism. 13 As individuals with mutations in ORC1 showed overlapping features with MGS, mutation analysis of ORC1 was performed in 33 individuals with MGS and revealed mutations in 4 individuals from three families. 13 Mutation analysis of other genes of this prereplication complex showed mutations in ORC4, ORC6, CDT1, and CDC6 in 14 individuals fro...

Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication

“…Thus, the two different sequences in Orc1 that confer specificity of inhibition of Cyclin E-CDK2 and Cyclin A-CDK2 kinase activities (R105 and the Cy motif, respectively) appear to be localized on the same surface of the BAH domain, away from the histone interaction surface. The R105Q mutation is present in seven of the 11 Orc1 patients recently analyzed (de Munnik et al 2012) and has the largest effect on Cyclin E-CDK2 and on centrosome and centriole copy number control. The E127 amino acid (E126 in mouse Orc1) (Fig.…”

“…5A, top panel; Zhang et al 2002;Kuo et al 2012). Most Meier-Gorlin syndrome patients (seven out of 11 recently characterized) have an Orc1 with a mutation that changed an arginine at amino acid 105 to a glutamine (R105Q) (de Munnik et al 2012). The presence of Orc1 mutations in the CID, and the fact that other microcephalic primordial dwarfism syndrome mutations map to other genes encoding centrosome-associated proteins, suggested further investigation of their effect on centriole and centrosome biology.…”

“…Recently, three studies reported that mutations in pre-RC proteins, including human Orc1, are associated with Meier-Gorlin syndrome, a form of microcephalic primordial dwarfism (Bicknell et al 2011a,b;Guernsey et al 2011;de Munnik et al 2012). Of the mutations reported in human Orc1 in Meier-Gorlin syndrome, the three mutations (F89S, R105Q, and E127G) occurred within the CID that contains a bromo-associated homology (BAH) domain (Fig.…”

“…Recently, mutations in Meier-Gorlin syndrome have been found in pre-RC proteins, including ORC subunits Orc1, Orc4, and Orc6, as well as Cdc6 and Cdt1 (Bicknell et al 2011a,b;Guernsey et al 2011;de Munnik et al 2012). Patients have primordial dwarfism, microcephaly, and developmental abnormalities in the ear and patella (Klingseisen and Jackson 2011).…”

“…Other developmental disorders that cause primordial dwarfism and microcephaly, including Seckel syndrome, have mutations in the centrosome proteins CPAP (CENP-J), PCNT, and CEP152, although defects in a few noncentrosome proteins such as ATM and IGF1 are also associated with microcephalic primordial dwarfism (Rauch et al 2008;Miyoshi et al 2009; Thornton and Woods 2009;Kitagawa et al 2011;Klingseisen and Jackson 2011;Sir et al 2011;Tang et al 2011). A survey of the mutations and phenotypes in 45 Meier-Gorlin syndrome patients demonstrated that compared with patients with mutations in Orc4, Cdc6, and Cdt1, all of the patients with mutations in Orc1 were of significantly shorter stature and had increased microcephaly and a significantly proportionally smaller head circumference and brain (de Munnik et al 2012). All but one of the patients with Orc1 mutations had normal intellect, and the one individual had a mild intellectual disability.…”