Premium
Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP 1 alterations with three novel mutations
Author(s) -
Madeira Joao LO,
Nishi Mirian Y,
Nakaguma Marilena,
Benedetti Anna F,
Biscotto Isabela Peixoto,
Fernandes Thamiris,
Pequeno Thiago,
Figueiredo Thalita,
Franca Marcela M,
Correa Fernanda A,
Otto Aline P,
Abrão Milena,
Miras Mirta B,
Santos Silvana,
Jorge Alexander AL,
Costalonga Everlayny F,
Mendonca Berenice B,
Arnhold Ivo JP,
Carvalho Luciani R
Publication year - 2017
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/cen.13430
Subject(s) - multiplex ligation dependent probe amplification , sanger sequencing , mutation , genetics , point mutation , biology , microbiology and biotechnology , medicine , gene , endocrinology , exon
Summary Background Mutations in PROP 1 , HESX 1 and LHX 3 are associated with combined pituitary hormone deficiency ( CPHD ) and orthotopic posterior pituitary lobe ( OPP ). Objective To identify mutations in PROP 1 , HESX 1 and LHX 3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). Design and Methods We studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP 1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation‐dependent probe amplification ( MLPA ) was applied to one familial case in whom PROP 1 failed to amplify by PCR . In the 13 patients without PROP 1 mutations, HESX 1 and LHX 3 were sequenced by the Sanger method. Results We identified PROP 1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302del AG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP 1 deletion in one family. We did not identify HESX 1 and LHX 3 mutations by Sanger. Conclusion PROP 1 mutations are a prevalent cause of congenital CPHD with OPP , and therefore, PROP 1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP , especially in populations with a high frequency of PROP 1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP 1 mutations is associated with the ethnic background of this cohort.