Homology study showed that this amino acid was highly conserved through species for the c.1041C>A and c.1151C>T mutations.

<p>Homology study showed that this amino acid was highly conserved through species for the c.1041C>A and c.1151C>T mutations.</p

Tertiary structure prediction of the wildtype protein (left column) and with the mutants.

<p>3D structure was predicted at Protein Homology/analogY Recognition Engine (PhyreEngine) from the Structural Bioinformatics Group, Imperial College, London, at <a href="http:www.sbg.bio.ic.ac.uk/phyre~/" target="_blank">http:www.sbg.bio.ic.ac.uk/phyre~/</a>. The plain arrows show the changes in the shape of the protein between the wildtype and p.P384L.</p

Clinical and hormonal data of patients with mutated <i>MAMLD1</i>.

<p>SD: standard deviation. ND: not determined. NA: not available. DHT: dihydrotestosterone. DHEA: dihydroepiandrsosterone. Parentheses indicate the standard deviation for height and weight and the normal range for hormone serum levels. Testes of 1–2 ml can be regarded as normal, as recently reported by Shibata et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032505#pone.0032505-Shibata1" target="_blank">[34]</a>.</p>*<p>It is notable that anti-mullerian hormone and inhibin were lowered in one case. <i>MAMLD1</i> is indeed reported to be expressed in Sertoli cells, as well <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032505#pone.0032505-Fukami1" target="_blank">[15]</a>.</p

Transactivation function of the variants of the MAMLD1 protein analyzed by the luciferase method.

<p>The activity is evaluated for pHes3-luc vector.</p

Incidence of exonic polymorphisms p.P359S and p.N662S, and relative haplotypes in normal controls and 46,XY DSD patients.

<p>Controls are combined with the published series (matched for ethnicity of patients and controls) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032505#pone.0032505-Kalfa1" target="_blank">[13]</a><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0032505#pone.0032505-Chen1" target="_blank">[14]</a>. The χ-square test was performed. When combining all patients with the p.662G polymorphism whatever the p.359 allele, this p.662G was significantly more frequent in 46,XY DSD patients: 27.1% (n = 19) vs. 6.8% (n = 40), <i>p</i> = 0.0001.</p

Electrochromatograms and pedigrees of the three patients with <i>MAMLD1</i> mutations.

<p>The black squares indicate patients with posterior hypospadias. All mutant sequences were controlled by wildtype (WT) DNA. Regarding case 1's family, only the members III-3 and II-4 were genotyped, as the other members in the pedigree declined genetic testing.</p

Height SDS during the first 2 years of GH treatment and at final height.

<p>Error bars are medians with interquartile ranges. Significant statistical differences between height SDS at baseline and others time points: *** P < 0.0001 (2-way repeated-measures ANOVA plus Bonferroni post-test).</p

Characteristics of patients with extra-pituitary malformations (syndromic group).

<p>SOD: septo-optic dysplasia, ASD: atrial septal defect, VSD: ventricular septal defect</p><p>Characteristics of patients with extra-pituitary malformations (syndromic group).</p

Evolution of the hormonal impairment according to the initial presentation.

<p>(A) Frequency of GH, ACTH and/or TSH deficiencies in neonates (n = 10) and patients with growth retardation, at baseline (n = 47) and at final height (n = 21). Significant statistical difference in the number of cases of combined pituitary hormone deficiency between groups of neonates and patients with growth retardation: ** P < 0.001 (chi square test). The gonadotropic axis was evaluated in neonates (during “mini-puberty”) and in patients of postpubertal age. LH/FSH deficiency was found in 9 of 10 neonates (90%) and 12 of 21 patients with growth retardation at final height (57%); this was not statistically different (P = 0.1522). (B) Evolution of ACTH, and TSH deficiencies throughout childhood in patients with growth retardation who reached their final height (n = 21). All patients had GHD at diagnosis.</p

Clinical and radiological characteristics at baseline of the 67 patients with PSIS and the subgroups.

<p>Values are medians (range) or percentages as indicated. P values were calculated using the Mann-Whitney test</p><p>Clinical and radiological characteristics at baseline of the 67 patients with PSIS and the subgroups.</p